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Chronic inflammation is a characteristic of obesity and is associated with accompanying insulin resistance, a hallmark of type 2 diabetes mellitus (T2DM). Although proinflammatory cytokines are known for their detrimental effects on adipose tissue function and insulin sensitivity, their beneficial effects in the regulation of metabolism have not drawn sufficient attention. In obesity, inflammation is initiated by a local hypoxia to augment angiogenesis and improve adipose tissue blood supply. A growing body of evidence suggests that macrophages and proinflammatory cytokines are essential for adipose remodeling and adipocyte differentiation. Phenotypes of multiple lines of transgenic mice consistently suggest that proinflammatory cytokines increase energy expenditure and act to prevent obesity. Removal of proinflammatory cytokines by gene knockout decreases energy expenditure and induces adult-onset obesity. In contrast, elevation of proinflammatory cytokines augments energy expenditure and decreases the risk for obesity. Anti-inflammatory therapies have been tested in more than a dozen clinical trials to improve insulin sensitivity and glucose homeostasis in patients with T2DM, and the results are not encouraging. One possible explanation is that anti-inflammatory therapies also attenuate the beneficial effects of inflammation in stimulating energy expenditure, which may have limited the efficacy of the treatment by promoting energy accumulation. Thus, the positive effects of proinflammatory events should be considered in evaluating the impact of inflammation in obesity and type 2 diabetes.
- inflammation
- energy expenditure
- insulin resistance
- anti-inflammatory therapy
- type 2 diabetes
obesity has reached epidemic proportions in many developed countries, including the United States. It induces marked insulin resistance and increases the risk of developing type 2 diabetes mellitus (T2DM) and other diseases (cardiovascular disease, some cancers, and asthma). One feature of obesity is a low-grade inflammation that likely originates in the expanding adipose tissue, and it is associated with infiltration of immune cells, including macrophages, lymphocytes, and leukocytes (22, 95, 131). The cytokines released from the inflammatory tissue affect the metabolic functions of several organs, including the liver, heart, muscle, and brain (46, 122). Proinflammatory cytokines released by the activated immune cells can impair insulin signaling in insulin-responsive organs and cause systemic insulin resistance, which increases the risk of developing hyperglycemia and T2DM. Insulin sensitizers such as thiazolidinediones (TZDs) have anti-inflammatory activity, which provides an additional rationale to pursue clinical studies to evaluate the efficacy of targeted anti-inflammatory therapeutics on T2DM (46, 95). In fact, anti-inflammatory therapies have been tested in many clinical trials to improve insulin sensitivity and restore glucose homeostasis.
However, the anti-inflammation therapies (anti-TNF, anti-IL-1, anti-IL-6, and salsalate) that will be discussed below have shown very limited efficacy with regard to improving insulin action and glucose homeostasis. While there could be many explanations (such as less efficacious than standard diabetes therapy, off-target effects, wrong patient population, etc.) for the limited benefit of anti-inflammatory therapies, one possibility is that our assumption that inflammation has only negative effects on insulin action and glucose homeostasis may not be correct. There might be some beneficial effects of inflammation in obesity. For example, inflammation plays an essential role in maintaining healthy adipose tissue through stimulating tissue remodeling (101). Inflammation increases energy expenditure and suppresses food intake, which would favor insulin sensitivity by limiting obesity (discussed below). Thus, the net outcomes of anti-inflammatory therapy on insulin sensitivity could depend on the extent to which the benefits outweigh the negatives in a given individual. In this review, we discuss the role of inflammation in adipose tissue remodeling and its impact on energy balance. We will use the beneficial effects of inflammation to explain the mixed results of the anti-inflammatory clinical trials that have been reported.
Why Does Obesity Increase Inflammation in Adipose Tissue?
White adipose tissue is a primary site of chronic inflammation in obesity and is characterized by expression of proinflammatory cytokines and infiltration of a variety of immune cells, including macrophages, T lymphocytes, B lymphocytes, natural killer cells, and neutrophils. (22, 95, 131). These immune cells, together with adipocytes and stromal vascular cells, constitute a cellular network that produces both proinflammatory and anti-inflammatory cytokines (40, 101, 132). While the proinflammatory cytokines are well known to impair insulin action in adipocytes, they are required for maintenance of angiogenesis, extracellular matrix remodeling, and clearance of dead cells in adipose tissue (15, 18, 40, 101, 129). These activities of inflammation are required to maintain a "healthy" microenvironment to sustain adipose tissue expansion. Angiogenesis is required for adipocyte differentiation and adipocyte function (17, 41). Inhibition of angiogenesis leads to suppression of adipose tissue growth, which has been shown to prevent obesity in mice (14). Recent studies suggest that proangiogenic factor (VEGF, vascular endothelial growth factor) and antiangiogenic factor (PEDF, pigment epithelium-derived factor) are elevated in plasma of obese humans and mice (20, 43, 116). In transgenic mice, adipocyte-specific overexpression of VEGF enhanced angiogenesis in adipose tissue and stimulated energy expenditure through fat "browning," which is associated with improved insulin sensitivity (128). In contrast, infusion of PEDF inhibited angiogenesis and impaired insulin sensitivity in mice, whereas neutralizing PEDF improved insulin action (20). Macrophages, the major inflammatory cells in adipose tissue, have been reported to facilitate adipocyte differentiation (90), control lipolysis (65), and augment brown fat function in adipose tissue in mice (88). In obesity, adipocyte expansion in size disrupts the interaction between adipocytes and the extracellular matrix in adipose tissue. Inflammation facilitates restoration of the balance by stimulating adipocyte lipolysis to attenuate cell expansion.
Adipose tissue hypoxia is considered the initiator of chronic inflammation in obese states (134, 146). A reduction in interstitial oxygen was first observed in adipose tissue of obese mice (147) and then confirmed in human and mouse obesity models (104, 146). In growing tissues, a transient hypoxia is a common signal in the stimulation of new blood vessel formation (angiogenesis). If the angiogenic response is insufficient to resolve the hypoxia, a chronic inflammatory response will be activated (146). Inflammation is one of a number of alterations that have been found in adipose tissue in obesity (Fig. 1). The others include endoplasmic reticulum (ER) stress, decreased adiponectin, elevated leptin, increased lipolysis, decreased adipogenesis, adipocyte death, and insulin resistance. There is no unifying mechanism for all of these alterations. Adipose hypoxia may explain most, if not all, of the alterations in the adipose tissue (Fig. 1). Insufficient blood supply is the underlying mechanism for the adipose hypoxia (see review in Ref. 145).
Hypoxia alters the balance between pro- and anti-inflammatory activities in adipose tissue. In cells, hypoxia induces expression of proinflammatory cytokines by activating transcription factors such as NF-κB (nuclear factor-κB) and HIF-1α (hypoxia-inducible factor 1α) in adipocytes and resident macrophages (147). Additionally, the local hypoxia may promote M2/M1 macrophage switching and induce leptin expression or adipocyte death to enhance the inflammatory response. M2 macrophages suppress the inflammatory response by secreting IL-10 and stimulate angiogenesis by producing angiogenic factors (37). In obesity, the differentiation of M2 into M1 macrophages is considered a major event that sustains chronic inflammation (76). In addition to the hypoxia hypothesis, there are other hypotheses for the origin of the inflammation in the adipose tissue (130). Yet, irrespective of the mechanism, most studies suggest that certain levels of inflammation are required for the maintenance of adipose tissue function by regulating extracellular matrix remodeling and adipocyte differentiation.
Inflammation: Impact on Energy Expenditure and Glucose Homeostasis
The primary cause of adiposity is a mismatch between energy intake and energy expenditure. Leptin and insulin play central roles in the regulation of energy balance in the body. Leptin induces satiety and augments energy expenditure to limit weight gain. In opposition, insulin induces energy accumulation and promotes weight gain. Yet, despite the marked increase in leptin in obesity, animals gain weight, presumably from central leptin resistance that is responsible for impaired control of food intake and energy expenditure. The energy surplus or weight gain is a major risk factor for insulin resistance, which triggers hyperinsulinemia. Adipose tissue inflammation is generally believed to contribute to the pathogenesis of insulin resistance through proinflammatory cytokines (see reviews, Refs. 46, 95, 122). However, the same cytokines stimulate energy expenditure and induce satiety and thus limit adiposity and improve glucose homeostasis. A role of inflammation in the control of energy expenditure will be discussed below.
We will examine the evidence from genetic and pharmacological studies in which both proinflammatory and anti-inflammatory cytokines have been tested in the regulation of energy balance. We recognize that the regulation of energy expenditure is complex and involves central and peripheral tissues (133). The proinflammatory cytokines to be discussed are interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNF-α), leptin, and IL-18. The anti-inflammatory cytokines and signaling molecules are IL-1 receptor antagonist (IL-1Ra), mitogen-activated protein kinase phosphatase-1 (MPK1), adiponectin, and IL-10. In addition, we will discuss the studies in which inflammatory signaling pathways (NF-κB and JNK) have been manipulated. The major points about inflammation in energy balance are outlined in Fig. 2. Since the negative effects of proinflammatory cytokines on insulin action and adipose tissue function have been extensively documented in several outstanding review articles (46, 95, 122), we will not reiterate the negative effects in this article.
Before discussing the cytokines, or signaling molecules, we will briefly discuss the impact of endotoxemia on glucose homeostasis. Recent studies suggest that endotoxemia, secondarily to increased gut permeability and dietary-induced alterations of the intestinal microbiome, may contribute to the chronic inflammation associated with obesity (12, 56). As in obesity, endotoxemia induces similar inflammatory events and, on the surface, has overlapping metabolic features with inflammation. Moreover, a number of clinical trials have tested the impact of anti-inflammatory therapy on mortality in septic individuals. Although the patient population of endotoxemia is significantly different from individuals with T2DM, similar strategies have been used to test the role of inflammation.
There is rich literature regarding the acute impact of endotoxin (LPS) on inflammation and metabolism. The inflammatory response to LPS includes expression of many cytokines that are also upregulated by obesity, although the kinetics and origin of the cytokines are different. Following LPS exposure, the primary source of circulating cytokines is resident macrophages in the liver and other highly vascular tissues. LPS is a potent activator of the hypothalamo-pituitary-adrenal axis and is known to induce leptin secretion (even in the absence of obesity). The glucose response to LPS is dependent on the dose and duration of exposure to LPS and the species involved (80, 126). In general, high doses of LPS cause profound hypoglycemia and insulin resistance; low doses of LPS generally cause hyperglycemia and insulin resistance. At first, a combination of hypoglycemia and insulin resistance seems like a contradiction. However, the hypoglycemia is a result of impaired hormone-stimulated hepatic glucose production and increased insulin-independent glucose uptake in multiple tissues in both humans and rodents (2, 80, 81, 144). The insulin resistance is related to impaired insulin action in the liver or muscle through both direct and indirect effects of LPS. Proinflammatory cytokines are believed to impair insulin signaling directly in multiple tissues. The indirect effects include low blood flow in insulin-sensitive tissues (85, 135), increased glucocorticoid secretion (2, 81), and concomitant activation of the autonomic nervous system. LPS inhibits food intake and increases energy expenditure. However, in rodents, energy expenditure may decrease and hypothermia can develop if the animal is not in a thermoneutral environment or in response to a high dose of LPS (67).
Endotoxin concentrations can transiently rise after a normal meal, and high-fat diets can induce a low-grade endotoxemia (12, 56), which is proposed as a risk factor for the chronic inflammation in obesity. The impact of chronic low-grade endotoxemia on metabolism has been reported in two studies. Chronic (28 days) treatment with a low dose of LPS (300 μg·kg−1·day−1) induced obesity in mice (12). The adiposity was observed in the absence of detectable changes in energy intake. Energy expenditure (and/or core body temperature) was not assessed in the study but was likely reduced by LPS. Interestingly, despite the presence of obesity and inflammation in LPS-treated mice, there was no systemic insulin resistance. In a cat study, LPS was infused for 10 days (96). Initially LPS induced insulin resistance (increased basal insulin). However, by day 10, despite evidence of persistent inflammation, insulin concentration returned to normal. Thus the effects of sustained LPS delivery on hepatic and peripheral glucose metabolism can differ markedly from the acute effect of LPS. The mechanism of weight gain in the two LPS models remains to be identified. The anti-inflammatory response that is triggered by the chronic proinflammatory response may play a role in the inhibition of energy expenditure in LPS-treated mice.
Clinical trials of anti-TNF therapies have been conducted but yielded limited benefit in septic patients. Recently, the only immunomodulatory drug (drotrecogin-α) approved specifically for the treatment of severe sepsis was withdrawn from the market for its poor efficacy (8, 110⇓–112). The reason for the limited efficacy of the drug is unknown. Several factors likely play a role, such as the timing and duration of therapy, patient heterogeneity, the therapeutic ability to access the site of inflammation, and the possibility of beneficial effect of TNF-α. Interestingly, timing of intervention is important. In rodents, if anti-TNF therapy was started before LPS administration, it was very effective. However, if it was given a few hours after LPS exposure, the anti-TNF therapy was not effective (7). Thus, anti-inflammatory approaches have not been very successful in improving outcomes in sepsis.
What we have learned from studies examining the impact of targeting inflammatory events in shaping the metabolic response to LPS or sepsis is that the net effect of inflammatory events on glucose homeostasis are dependent on both the duration of exposure and the magnitude of the inflammatory response. Moreover, while inflammatory mediators can impair insulin action, they also directly reduce blood glucose by impairing hepatic glucose production and augmenting peripheral glucose disposal independently of insulin. This complex interaction may explain the very dynamic and time-dependent effect of chronic inflammation on glucose homeostasis. If one considers that low-grade endotoxemia may contribute to obesity-associated inflammation, anti-inflammatory therapies should be able to attenuate the metabolic disorders in obesity. However, anti-inflammatory therapies have not been very effective. If the beneficial effect of targeting inflammation in sepsis is offset by the side effects of the therapies or time window of the intervention, similar challenges will present in the anti-inflammatory therapies that are designed to improve glucose homeostasis without negative consequences in obese and diabetic individuals.
Targeted modulation of pro- and anti-inflammatory cytokines and hormones.
As the first proinflammatory cytokine reported in adipose tissue, TNF-α has been extensively documented as a participant in the pathogenesis of insulin resistance (47, 48). In cellular models, TNF-α inhibits insulin signaling through activation of several serine kinases including JNK (c-JUN NH2-terminal kinase), IKK, S6K (ribosomal protein S6 kinase 1), etc. (32, 115, 150). In adipose tissue, TNF-α is primarily produced by resident macrophages. The metabolic activity of TNF-α is complex, as indicated by comparing the phenotype of global TNF-α KO and TNF-receptor KO mice. While both mice have little or no phenotype on a chow diet, on a high-fat diet (HFD) TNF-α KO mice have normal weight gain. In contrast, the TNF receptor KO mice have a blunted weight gain when the receptor 2 (R2) but not R1 receptor is removed (120, 143). Diet-induced hyperinsulinemia was exacerbated when both receptors were removed. This suggests that TNF-α may maintain, rather than aggravate, insulin action in vivo. A more careful analysis of the TNF receptor KO mice (100) using littermate controls revealed that they are prone to obesity and have a low metabolic rate. Interestingly, when TNF-α is reconstituted only in the adipose tissue using the aP2 promoter in TNF-α KO mice, the transgenic mice exhibit less adiposity at 20 wk of age (142), suggesting a role for TNF-α in the maintenance of energy balance. Although ex vivo insulin action was impaired in adipose tissue, systemic insulin sensitivity was improved in the mice, as indicated by a low level of fasting insulin. In a more severe insulin resistance model, such as the db/db mouse, loss of TNF-α receptor has no phenotype (120). In summary, TNF-α has profound effects on adipose tissue biology and insulin signaling in adipocytes, but its contribution to systemic insulin resistance during obesity is limited.
The IL-1 superfamily includes more than 30 members. Of these, IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1Ra) have been reported to regulate energy metabolism and glucose homeostasis. IL-1α and IL-1β share the same cell membrane receptor (type I receptor) and trigger similar intracellular signaling pathways. IL-1 activity is regulated both transcriptionally and posttranscriptionally. The latter occurs via proteolytic cleavage of pro-IL-1β by the inflammasome (55). In addition, IL-1 competes for receptor occupancy with the receptor antagonist IL-1Ra.
IL-1 modulates glucose homeostasis by impairing insulin signaling, modulating insulin secretion, augmenting insulin-independent glucose uptake, increasing energy expenditure, and stimulating autonomic nervous system activity (58, 70, 97, 107). Depending on the dose, IL-1 can induce hypoglycemia or hyperglycemia (70, 138). Moreover, IL-1β can inhibit insulin secretion in β-cells and induce islet failure (4). Thus, even though IL-1 can directly impair insulin action in vivo, an assortment of responses can be manifested, some of which actually improve rather than aggravate glucose homeostasis. IL-1 also can limit obesity by augmenting energy expenditure (78, 83). When superphysiological doses of IL-1 (IL-1α or IL-1β) are given directly (intracerebroventricularly) into the central nervous system, energy expenditure and body temperature increase, and food intake decreases (83), inducing a negative energy balance. IL-1 administration activates the hypothalamic-pituitary-adrenal axis, increasing plasma corticosterone and adrenocorticotropin, and decreases spontaneous physical activity in rats. Continuous injection of IL-1 into the central nervous system for 5 days reduces body weight secondarily to anorexia and an increase in energy expenditure (83). Although those observations were made with nonphysiological levels of IL-1, the studies consistently support the body's physiological response to IL-1. Thus, in conditions such as obesity, where IL-1 activity is chronically elevated, interventions that inhibit IL-1 activity may, in fact, induce positive energy balance and aggravate glucose homeostasis.
The importance of IL-1 in regulating energy metabolism is supported by the phenotype of mice lacking either IL-1Ra or the IL-1 receptor (33, 78). IL-1Ra is an anti-inflammatory protein secreted by adipose tissue and other tissues (51). IL-1Ra acts to block IL-1 interaction with its receptor. Plasma IL-1Ra is elevated in obesity (82). IL-1Ra KO mice have enhanced IL-1 activity, and the mice are resistant to obesity (78). Their energy expenditure (normalized for body weight) is enhanced, and they are protected from HFD-induced insulin resistance (124, 125). Given that the IL-1Ra KO mice are smaller than the wild-type (WT) controls, more advanced statistical analysis is required to normalize the energy expenditure data (53, 54). Inhibition of IL-1 activity by injection of recombinant IL-1Ra leads to insulin resistance in mice (124). In IL-1R KO mice, IL-1 is unable to stimulate energy expenditure, and the mice have increased (1.5- to 2.5-fold) visceral and subcutaneous fat (33). This was accompanied by hyperglycemia and insulin resistance. Thus, some of the IL-1 activity seen during obesity may serve to limit adiposity and reduce the risk of developing T2DM.
IL-6 is elevated in plasma and in adipose tissue in obesity (29, 57). The impact of IL-6 activity on energy and glucose metabolism is suggested by the phenotypes of both the IL-6 KO (137) and STAT3 (signal transducer and activator of transcription 3) KO mice (49). STAT3 is a transcription factor that is activated by IL-6. Global ablation of IL-6 leads to adult-onset obesity and insulin resistance (137). In transgenic mice, IL-6 overexpression in skeletal muscle stimulates energy expenditure and reduces food intake, which limits adiposity (28). Exercise is an important lifestyle intervention to control weight gain. Interestingly, as a myokine, IL-6 is secreted by contracting muscle and is elevated two- to threefold in the circulation during exercise (105, 106). The increase in IL-6 may help amplify exercise-induced lipolysis in adipose tissue; the mobilized fatty acids are then oxidized by the working muscle (106). The impact of IL-6 on glucose metabolism is controversial. IL-6 infusion does not reduce insulin sensitivity in human subjects (68), yet it does so in mice (59, 63, 64). In mice, suppression of IL-6 signal transduction by liver-specific STAT3 ablation leads to hepatic insulin resistance (49). Basal IL-6 may be required in the maintenance of glucose homeostasis by restraining gluconeogenesis. As IL-6 has beneficial effects on glucose metabolism and on energy balance during exercise, anti-IL-6 therapy may have unfavorable consequences in obesity and T2DM.
Leptin secretion increases as adipose tissue expands. Leptin limits weight gain by reducing food intake and increasing energy expenditure (84). However, obesity is associated with leptin resistance, which is manifested as hyperleptinemia. It is unclear whether the resistance is a primary contributing factor to the obesity and/or is secondary to the higher leptin tone. Moreover, it is not known whether the leptin resistance extends to tissues other than the brain. Leptin resistance is thought to primarily occur in the brain. Leptin can be proinflammatory. Leptin induces the expression of proinflammatory cytokines in macrophages and T cells (74, 75, 79) and stimulates macrophage phagocytosis and monocyte proliferation (30, 74). Leptin also activates other signaling pathways used by proinflammatory cytokine receptors, including MAPKs (mitogen-activated protein kinases p38 and ERK) (77, 86), JAK/STAT3 (6, 136) and phosphatidylinositol 3-kinase (PI3K) (77, 141). Leptin expression is induced by inflammatory mediators (39, 119, 155). The signaling pathway and expression pattern suggest that leptin may mediate proinflammatory responses.
The protein structure of leptin is similar to that of other proinflammatory cytokines including IL-6, IL-11, IL-12, LIF, G-CSF, etc. (19), which may permit cross-talk of those cytokines with the leptin receptor. Leptin stimulates T cell proliferation and Th1 differentiation (5, 79), controls regulatory T lymphocytes (Treg) in adipose tissue (24), inhibits anti-inflammatory cytokine expression (IL-4 and IL-10) (79), and promotes Th1-mediated inflammatory responses such as experimental colitis and collagen-induced arthritis (9, 123). These inflammatory responses are reduced in ob/ob or db/db mice. This may be due, in part, to the elevated corticosterone secretion in these mice (44). However, leptin is not absolutely required for the chronic inflammation in adipose tissue in obesity. ob/ob mice exhibit comparable adipose inflammation to WT obese mice (147). Low-energy expenditure, hypothermia, and cold intolerance are characteristics of leptin deficiency in ob/ob mice and leptin receptor-deficient (db/db) mice. Leptin controls food intake and energy expenditure through its actions in the brain. Leptin also acts on peripheral tissues (such as pancreatic islets) to regulate energy balance and feeding behavior. In obesity, leptin resistance in the brain and islets contributes to sustained weight gain and is involved in development of hyperleptinemia. A high level of leptin may promote chronic inflammation by inhibiting expression of anti-inflammatory cytokines and inducing proinflammatory cytokines in T cells and macrophages. We are unaware of any study reporting leptin resistance in immune cells in obesity.
IL-18 is another member of the IL-1 superfamily. In obese and T2DM subjects, the plasma concentration and adipose tissue expression of IL-18 are elevated (25). A major function of IL-18 is to induce IFNγ expression by T cells; however, IL-18 also has effects on adipose tissue and brain. IL-18 suppresses angiogenesis through IFNγ-dependent expression of interferon-γ-inducible protein 10 (IP-10). The specific role of IP-10 in adipose tissue is unclear (13). Global IL-18 inactivation in mice increases the risk for obesity, hyperphagia, and insulin resistance (87). Administration of recombinant IL-18 (rIL-18) intracerebroventricularly inhibited food intake, reversed hyperglycemia, and corrected T2DM subjects, IL-18 resistance may be present (154). Thus, elevated IL-18 may serve a protective role in obesity to limit adiposity.
Adiponectin is an adipokine that has anti-inflammatory activity. Adiponectin concentration is reduced in plasma of obese subjects, and the reduction is associated with an elevation in chronic inflammation (23). Adiponectin expression in adipocytes is reduced by hypoxia and proinflammatory cytokines (146). In ob/ob mice, fat-specific overexpression of adiponectin makes the transgenic mice more obese, but the mice are healthy compared with their ob/ob littermates (61). Adiponectin has been reported to inhibit lipolysis in adipocytes (109). Despite the exaggerated adiposity in adiponectin-overexpressing mice, adipose tissue inflammation is not elevated. This is presumably due to the increased adiponectin expression in the mice (61). In vitro, adiponectin inhibited the inflammatory response in macrophages via increasing anti-inflammatory cytokines such as IL-10 (103). In cells, adiponectin induces activities of several anti-inflammatory signaling molecules, including SOCS3 (suppressor of cytokine signaling 3) (27), A20 (TNF-induced protein-3) (27), and AMPK (AMP-activated protein kinase) (98). These cellular activities likely explain the anti-inflammatory effects of adiponectin. Thus, the anti-inflammatory activity of adiponectin is closely associated with facilitation of energy accumulation and inhibition of energy expenditure.
IL-10 is a classical anti-inflammatory cytokine that suppresses the signal transduction of proinflammatory cytokines. The plasma concentration of IL-10 is reduced in obesity (23); the mechanism is not known. IL-10 expression is induced by proinflammatory cytokines such as TNF-α. IL-10 is mainly produced by M2 macrophages and Th2 lymphocytes. In obese mice, IL-10 is increased when M2 macrophages are stimulated by TZD treatment (76, 92). In physiological settings, IL-10 is required to resolve inflammation. In mice, global inactivation of IL-10 increases the risk of inflammation; KO mice suffer from chronic enterocolitis (69). The KO mice have less fat tissue and lower body weight relative to the control mice (69). Whether IL-10 alters food intake and/or energy expenditure has not been evaluated. Interestingly, hematopoietic inactivation of IL-10 did not alter the response of the mice to an HFD (66), suggesting that the low adiposity of IL-10 KO mice is not due to loss of IL-10 in blood cells or macrophages. IL-10 infusion improved insulin sensitivity in rodents (59). In transgenic mice, overexpression of IL-10 in skeletal muscle decreased local inflammation and improved insulin sensitivity in response to an HFD despite similar adiposity (45). In summary, reduction of plasma IL-10 may contribute to the elevation in chronic inflammation in obesity. Its impact on glucose homeostasis and energy balance is less clear in obesity where IL-10 is decreased.
Targeted modulation of inflammatory signaling pathways.
The reality is that multiple cytokines or adipokines are altered in obesity, and metabolic responses to obesity involve more than one cytokine. The cytokines discussed above do not act in isolation. One proinflammatory cytokine may induce expression of other cytokines during an inflammatory response. At the same time, the proinflammatory cytokines induce expression of anti-inflammatory cytokines, which tends to dampen the overall inflammatory response. Based on the metabolic phenotypes of the mouse models discussed above, anti-inflammatory cytokines inhibit energy expenditure and promote weight gain by eliminating the metabolic activities of proinflammatory cytokines. Thus, we propose that, during weight gain, the anti-inflammatory factors play a dominant role. We refer to this physiological state as "inflammation resistance" (148). This condition likely occurs in the early stage of obesity and limits energy expenditure, thereby facilitating weight gain. In this section, we focus on intracellular signaling molecules that integrate pro- and anti-inflammatory cytokine activity to control energy balance.
Mitogen-activated protein kinase-1 (MKP-1) is an anti-inflammatory intracellular kinase that inhibits MAPK (p38, JNK, and ERK). In rodents, MKP-1 expression is increased in response to HFD. In global MKP-1 KO mice, MAPK activation (p38, JNK, and ERK) is amplified in response to various stresses such as LPS, serum growth factors, JNK activator (anisomycin), and osmotic stress (16, 89, 139, 152). The mice exhibit a strong proinflammatory response with elevations in TNF-α and IL-6 (16). As a result, the KO mice are more susceptible to endotoxin shock. The heightened inflammatory status in MKP-1 KO mice is associated with higher energy expenditure and resistance to diet-induced obesity (140). MPK1 induces p38 activation, and this mechanism may inhibit hepatic glucose production. In obese mice, p38 MAPK is reported to inhibit gluconeogenesis through activation of X-box binding proteins (XBPs) (72). p38 phosphorylates the spliced form of X-box binding protein-1 (XBP-1s), leading to their nuclear translocation. In the nucleus, XBP-1s inhibits gluconeogenesis by targeting Forkhead box O1 (FoxO1) (153). Thus, loss of anti-inflammatory signaling molecules results in a net increase in proinflammatory tone that increases energy expenditure and makes mice resistant to obesity.
NF-κB AND IKKβ.
The IKKβ/NF-κB signaling pathway controls the expression of the major proinflammatory cytokines. It is activated by many obesity-associated factors such as inflammation, hypoxia, ER stress, diacylglycerol, ceramide, etc. (146). This signaling pathway has been investigated in several studies using transgenic mice to understand the relationship between inflammation and insulin resistance (3, 10, 11, 113, 149). Those studies suggest that an increase in IKKβ/NF-κB activity may induce systemic insulin resistance or hepatic insulin resistance. However, the relationship of insulin resistance and energy expenditure was not carefully examined in the majority of those studies. This issue was addressed in our studies of two lines of NF-κB transgenic mice. We enhanced NF-κB activity by fat-specific overexpression of the NF-κB p65 subunit (aP2-p65 mice) or by (globally) deleting the NF-κB p50 subunit in p50 KO mice (31, 132). In both models, NF-κB tone was enhanced, and inflammation was increased in the mice on either a regular chow diet or HFD. The resultant inflammation increased energy expenditure and reduced adiposity in mice on HFD (31, 132, 151). Insulin sensitivity was not impaired in the mice on a chow diet and was improved in the mice on HFD. The observations were extended into fat-specific IKKβ-overexpressing mice that have been recently reported by another group (50). The fat-specific IKKβ mice exhibited an increase in energy expenditure and resistance to diet-induced obesity. Inflammation in adipose tissue failed to induce systemic insulin resistance in the mice on the regular chow diet or an HFD. Thus, inflammation in those fat-specific IKKβ/NF-κB mice provides beneficial effects in the control of adiposity and insulin resistance.
The beneficial activity of inflammation is supported by studies examining the impact of IKKβ in knockout mice (3, 38). Insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp in mice in which IKKβ was inactivated in myeloid cells (including macrophages and myeloid cells) (3). After 7 wk on an HFD, insulin sensitivity was improved in KO mice, and the change was associated with low adiposity. In a later study, the mice were found to have a heightened inflammatory response with elevated plasma IL-1β and greater lethality in response to endotoxin (38). Thus, IKKβ inactivation in myeloid cells generates a proinflammatory mouse model, in which insulin sensitivity was improved. This proinflammatory status might have played a role to attenuate weight gain. Although not discussed by the authors, the inflammation likely contributed to the improved insulin sensitivity in the mice on an HFD (3). Thus, the studies suggest that, if a proinflammatory state is created in vivo, the inflammation may enhance energy expenditure to protect the animals from diet-induced obesity and insulin resistance.
The serine kinase JNK1 that is activated by ER stress, inflammation, and lipotoxicity is believed to contribute to obesity-induced insulin resistance. JNK1 phosphorylates IRS-1 (Ser307 in rodent and Ser312 in human IRS-1) in cellular models, and global JNK1 KO mice are more sensitive to insulin (1, 99). However, a recent study of the liver-specific JNK KO mice demonstrates that loss of JNK1 impairs hepatic insulin sensitivity and predisposes the liver to steatosis when mice are placed on an HFD (117). In a separate study, activation of JNK1 by inactivating XBP1 improves insulin sensitivity in the liver (52). In contrast, JNK1 activation in other tissues (adipose tissue, skeletal muscle, and brain) impairs insulin action (118). These results suggest that JNK-dependent inflammation may regulate insulin sensitivity in a tissue-specific manner.
Anti-Inflammatory Therapy in Clinical Trials
The association of inflammation with insulin resistance in obesity suggests that inflammation may contribute to the pathogenesis of T2DM. This is supported by the fact that insulin sensitizer thiazolidinediones (TZDs) have anti-inflammatory effects, and inflammatory cytokines can induce insulin resistance in cellular and animal models (46, 95). In the past two decades, anti-inflammatory therapies have been used to improve insulin sensitivity in more than a dozen small clinical trials (Table 1). Most of the anti-inflammatory drugs are those that are routinely used in the treatment of rheumatoid arthritis, such as TNF-α antibodies (Etanercept, Infliximab, Humira, etc.) (62, 73, 93, 114), an IL-1 antibody (XOMA052) or inhibitor (Anakinra) (71), an IL-6 antibody (Tocilizumab) (94, 121), and an inflammation suppressor (salsalate, a dimer of salicylic acid) (26, 91). The therapeutics reduced inflammation in the patients in all of the clinical trials, as indicated by a decrease in the inflammatory markers C-reactive protein and IL-6. However, the therapeutic efficacy of improving insulin sensitivity remains uncertain.
Anti-TNF-α therapy was the first among those tested in clinical trials. There were more than 10 published studies for anti-TNF-α therapies in diabetic patients between 1996 and 2011 (Table 1). The drugs include Infliximab, Etanercept, and Humira (62, 73, 93, 114). Unfortunately, the therapy never entered the stage of large, multicenter trials due to inconsistent or negative results (93, 102). The therapy improved insulin sensitivity in patients with rheumatoid arthritis (36, 62, 114), but it was ineffective in diabetic patients without rheumatoid arthritis (73, 93, 114, 127). The discrepancy is likely related to the cortisone that was used in the management of rheumatoid arthritis in the diabetic patients. These studies suggest that TNF-α is not a good target in the improvement of insulin sensitivity or glucose disorder in T2DM patients.
IL-1 inhibitors improved glucose homeostasis in two of three small trials (Table 1). However, β-cell function, but not insulin action, was improved in the two trials. In the third trial, the IL-1 blocker (MOXA 052) failed to give the expected effects in the improvement of insulin resistance and glucose disorder (Table 1). Currently, the IL-1 antibody ACZ885 is being tested in a large clinical trial (600 subjects, NCT00900146*), and the final results are not yet known (22).
The impact of an IL-6 signaling inhibitor, Tocilizumab, on glucose homeostasis was evaluated in rheumatoid arthritis patients (94, 121). Tocilizumab improved glucose homeostasis (decreased Hb A1c) in diabetic patients and improved insulin action (decreased HOMA-IR) in nondiabetic subjects (94, 121). In the studies, the patients were receiving prednisolone for the management of rheumatoid arthritis. This makes the data interpretation complex, as prednisolone induces insulin resistance. The studies are not sufficient to suggest that IL-6 is a good target in the control of insulin resistance hyperglycemia in T2DM patients.
Salsalate, a dimer of salicylic acid, is used in the treatment of rheumatoid arthritis and osteoarthritis. Sodium salicylate (aspirin) at high doses improves insulin sensitivity in humans and mice (60, 149). Aspirin inhibits multiple serine kinases that phosphorylate IRS-1 in the suppression of the insulin signaling pathway (32). A recent study suggests that salicylate activates AMPK (AMP-activated protein kinase) through a direct interaction with AMPK protein, which is observed in the control of blood lipids (42). Aspirin also inhibits the expression of multiple inflammatory cytokines including IL-1 and TNF-α. The therapeutic value of aspirin is limited by the increased bleeding risk at the high dosages required to generate the metabolic effects. To overcome this weakness, salsalate (related to aspirin in structure) was chosen in diabetic clinical trials for its safety record in the treatment of rheumatoid arthritis (26, 34, 91). There have been reports from five small clinical trials using salsalate (Table 1). Insulin sensitivity (35) and glucose control (34) were improved in two small studies in T2DM subjects. Insulin concentration also was improved in young, obese, nondiabetic subjects (26). Glucose homeostasis was not evaluated in another study (91). A large trial for salsalate (284 subjects, NCT00799643*) is ongoing, but the preliminary results presented at a recent national meeting (American Diabetes Association) were that salsalate improved Hb A1c but did not change insulin sensitivity as assessed by fasting insulin and glucose. The improved Hb A1c was associated with an elevation in plasma insulin in the subjects. The results do not provide support to the role of inflammation in the pathogenesis of insulin resistance.
Statins are widely used in the control of blood cholesterol. In addition to the reduction of cholesterol, they also downregulate activities of several transcription factors, including NF-κB, AP-1, and HIF-1α, in the inflammatory pathway (21). The impact of statins on glucose metabolism and insulin sensitivity has been examined in a meta-analysis of more than 90,000 patients (108) who participated in major cardiovascular clinical trials (Table 1). The analysis reveals that statin therapy is associated with a 9% increase in the risk for developing T2DM. Compared with a moderate dose, high-dose statins exacerbate the risk. In these trials, participants did not have diabetes prior to therapy. Although statins are not the classical anti-inflammatory medicines, and the mechanism of statin-associated risk for diabetes is unknown, the anti-inflammatory activities of statins may contribute to the increased risk of T2DM in the study.
Our conclusion is that anti-inflammatory therapies are not very efficacious in improving insulin sensitivity in clinical trials. The therapies exhibit modest activities in improving glucose metabolism in some studies. The reason for the low efficacy is unknown. We propose that accounting for the beneficial effects of inflammation may be the key to understanding why obesity-associated inflammation is not as bad as we originally believed.
Many studies suggest that inflammation is a compensatory response in obesity. It has both positive and negative metabolic effects that impact energy expenditure, glucose homeostasis, and insulin action. Theoretically, the metabolic impact of inflammation is determined by the tissue location, the profiles of inflammatory mediators, and the cell types involved. Inflammation can increase energy expenditure and limit food intake as well as improve insulin sensitivity (148). This possibility has been supported by observations in many animal studies, which help us to gain a balanced view of inflammation. We recognize that those animal studies have limitations in terms of clinical relevance. However, the studies do help us to gain insight into the nature of obesity-associated inflammation. The negative impact of inflammation has been well documented in the regulation of glucose and lipid metabolism in obesity, and it has been the foundation of rationale for anti-inflammatory therapies in T2DM patients. Unfortunately, the therapies, in general, have done little to improve insulin sensitivity and glucose homeostasis, especially compared with the standard of care for individuals with diabetes. Currently, there is no consensus as to why the anti-inflammatory therapies have largely been unsuccessful. We propose that the positive activity of inflammation may be the key. Although the relative significance of the positive and negative effects of inflammation remains to be determined in obesity and T2DM, the evidence does not suggest that inflammation is a good therapeutic target to improve insulin sensitivity. Currently, the anti-inflammatory approaches cannot distinguish between the positive and negative effects of inflammation.
Several potential areas have been indicated in this review concerning future directions in obesity-associated inflammation. These areas deserve to be explored further. If inflammation prevents energy accumulation in obesity, why does obesity occur in the presence of inflammation? In the course of weight gain, does the anti-inflammatory activity become a dominant player in controlling energy balance and glucose homeostasis? Does the inhibition of islet function by inflammation have negative or positive effects on energy balance in obesity? As physical exercise is associated with chronic inflammation (e.g., elevated IL-6), should proinflammatory approaches be considered a part of the antiobesity strategy? Answers to these questions may lead to development of new approaches in the treatment of obesity and T2DM.
J. Ye is supported by National Institute of Diabetes and Digestive and Kidney Diseases grants (DK-085495 and DK-068036). O. P. McGuinness is supported by projects including the Vanderbilt Diabetes Research and Training Center (DK-020593), the Vanderbilt Mouse Metabolic Phenotyping Center (DK-059637), and RO1 projects (DK-043748 and DK-078188).
No conflicts of interest, financial or otherwise, are declared by the author(s).
Author contributions: J.Y. conception and design of research; J.Y. prepared figures; J.Y. and O.P.M. drafted manuscript; J.Y. and O.P.M. edited and revised manuscript; J.Y. and O.P.M. approved final version of manuscript; O.P.M. analyzed data.
We highly appreciate comments from Dr. George Bray, Dr. Barbara Kahn, and Dr. Frank Greenway. J. Ye and O. P. McGuinness are the guarantors of this work, had full access to all the data, and take full responsibility for the integrity of the data and accuracy of data analysis.
- Copyright © 2013 the American Physiological Society
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text: Profile Topics Started Replies Created Favorites Forum Replies Created Viewing 3 posts - 1 through 3 (of 3 total) Author Posts November 9, 2011 at 4:29 am in reply to: RSS Feeder Problems #52270 gingerichadamParticipant How do i just remove the RSS link? Thanks in advance October 19, 2011 at 6:25 pm in reply to: Adjusting Slideshow Speed #54315 gingerichadamParticipant I'm as blind as a bat, thank you sir September 19, 2011 at 3:57 am in reply to: RSS Feeder Problems #52268 gingerichadamParticipant Sidenote as well: is it possible to override the shortcode stylings within individual pages? Thanks Author Posts Viewing 3 posts - 1 through 3 (of 3 total)

subset: commoncrawl


text: Hey guys! Has anyone visited or purchased birds from Chickens Galore in Norco, Ca? I'm interested in getting some standard and specialty breed layer chicks (welsummer, gold laced wyandotte, easter eggers, ameraucanas, blue/lavender orpingtons, anaconas, silkies, blue hamburg, & blue andalusians). I don't necessarily want all of those breeds but, a few would do. Also, I am super open to purchasing these pullets from any other reputable, recommended breeder within the oc, los angeles, and san bernardino county areas (I live in Upland, Ca right now). Any information is good information!


text:
Obama plans Monday Minnesota visit
ST. PAUL -- President Barack Obama plans a southern Minnesota visit next week as part of a Midwestern rural tour.
The National Journal reports that Obama plans stops in Minnesota, Iowa and Illinois as part of a Monday-through-Wednesday bus tour announced earlier. Details for the Minnesota and Illinois visits have not been announced.
After the Midwest swing, Obama plans his family's annual New England trip to Martha's Vineyard.
Obama is to be in Minnesota Monday. On Tuesday, the president heads to Peosta, Iowa, where he will hold a rural economic forum at the Northeast Iowa Community College.
The rural trip wraps up in Illinois Wednesday.
The Journal quotes Obama Press Secretary Jay Carney as saying the bus trip is to see "what's going on in their local economies, what they think Washington can and should do to enhance economic growth, enhance job creation in their parts of the country."
Carney said that Obama "looks forward to talking to the folks about growing the economy, creating jobs."
The trip is being called an official visit, not a campaign event.
Don Davis reports for Forum Communications Co.


text:
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Get 10% Cashback in Westside Dollars
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Nutone 78W Fan Wall Control features 4-speed no-hum ceiling fan speed control and is for use with all Nutone Series Ceiling Fans. With this 120V AC, 1.5 Amp, white finish fan control, comfort and convenience is just a touch a way. Note: One wall control per fan.
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Loncego-The original version – made in Germany!
There are more and more highly satisfied users, EMS studios, personal trainers, wellness institutions, physiotherapists, and sports physicians trusting in the EMS technology of Loncego – on a worldwide basis.
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We have very precise ideas regarding a successful EMS training and continue to improve our product lines to meet your needs.
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We carefully plan every detail from the initial idea up to its production phase and final user delivery and training.
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text:
Kai Ryssdal: The Census Bureau told us not too long ago that home ownership in this country has fallen to the lowest level in more than a decade. Not to cast aspersions on the good people at the census, but a better timeframe might be four decades. If you count all those people who aren't paying their mortgages right now, home ownership is as low as it's been since 1965.
That's the analysis from Morgan Stanley. And the way the U.S. housing market is right now, the question that follows is: Is that such bad thing?
Marketplace's Amy Scott reports.
Amy Scott: The official home ownership rate is about 66 percent. Minus those delinquencies, you get 59.7 percent. Morgan Stanley's Oliver Chang says foreclosures take so long these days, they're slow to show up in the numbers.
Oliver Chang: So we believe that the seven-and-a-half million people that are delinquent probably should not be counted as homeowners because in a more normal environment, they would already no longer be a homeowner.
No matter how you measure it, home ownership has fallen from its official peak: 69 percent in 2004. Chang says as a result, the U.S. is becoming a society of renters.
Chris Thronberg: The big question here is: Why do we care so much? What is wrong with renting?
That's analyst Christopher Thornberg with Beacon Economics. Advocates of the tarnished American Dream say ownership creates more stable communities and essentially forces families to save money. But Thornberg -- a homeowner -- says buying a house is sort of like buying a flatscreen TV. It's a luxury, not a necessity.
In New York, I'm Amy Scott for Marketplace.


text:
hmmm...think I will iron my scraps in the scrap bag to get them ready to cut.
Welcome to the Quilting Board!
hmmm...think I will iron my scraps in the scrap bag to get them ready to cut.
Will you iron mine for me too since your wide awake? Hope you can fall back asleep soon.
i'm back up too... but I aint gonna be ironing...
I haven't gone to bed yet, have too much to do, so I am sitting at the computer as any good night owl would be.
Well now I am tired..I even cut up a bunch of 5 inch charms...ready to take a nap before going to work...LOL that worked like a charm.
:lol:Originally Posted by carolaug
Great, productive use of your time. Gives you a head start on something new (smile).
not sure that wide awake is true here, but got to check the QB before heading to work shortly!
Coffee, check, read QB, check, wait for everyone else to wake up, maybe.
I'm awake but it's 5:52AM mountain time.Connie in CO


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text:
Ellsworth wins three at New Richmond quad
The Ellsworth volleyball team picked up three victories at a quad Tuesday in New Richmond.
The Panthers won each match 2-1 beginning with a 25-13, 30-28, 16-18 marathon match against Durand. Ellsworth (4-1) followed that with a 25-19, 25-16, 14-16 win over Prescott and a 25-18, 25-17, 17-19 win over New Richmond.
Senior Abbey Ristow finished with 46 kills for the evening for the Panthers. Senior Jessy Tingelstad had 40 assists and sophomore Olivia Helmer added 21 assists.
"When we got the pass up it was a pretty game," Panthers head coach Tanya Powers said. "We were quicker on our feet, which was nice to watch."
Ellsworth faces River Falls Thursday in River Falls.


text:
The politics around immigration reform grows more heated with the state of Arizona vowing to enforce federal law. But opponents say the new Arizona law will lead to profiling of Mexican Americans. Two prominent experts on immigration talk about why consensus may be building to change immigration law.
The challenge of immigration reform
Politics St. Paul, Minn. ·


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text:
Perhaps the most promising pitch at Petco Park Thursday night wasn't thrown by Tim Stauffer or caught by Nick Hundley.
Although Stauffer and Hundley were keys to the Padres 3-1 victory over the Florida Marlins before 18,403, a pair of California teenagers stole the show during the pregame festivities.
Joe Ross lobbed a ceremonial first strike to Austin Hedges.
It is the Padres hope that three or four years down the road, the battery of Ross to Hedges will be prominent at Petco Park. Earlier Thursday, the recent high school graduates signed professional contracts worth $5.75 million in bonuses.
Ross, a right-handed pitcher and the 25th overall pick of June's draft, received $2.75 million for his signature.
Hedges, the 82nd overall pick despite being regarded as the top high school catcher in the land, celebrated his 19th birthday by formally signing a contract worth $3 million.
Last Monday night, both chose to launch their professional careers with the Padres rather than attend UCLA.
"They were going to be roommates at UCLA, now they're going to be roommates in Arizona," said Padres assistant general manager Jason McLeod.
Both Ross and Hedges will report to the Arizona Rookie League Padres and remain in Peoria through October for the Arizona Instructional League.
Although Ross is from Oakland and Hedges from San Juan Capistrano, Thursday night was not the first time they have been paired on a field.
Last summer, Hedges caught Ross for two innings in a high school All-Star game in Florida.
"He's the best catcher I've ever seen," said Ross of Hedges.
"We had a connection," Hedges said of working with Ross. "We were on the same page as soon as we went out there. He was throwing 95, 96. Afterwards we talked and I had committed to UCLA and then he committed."
Ross is not alone in his assessment of Hedges.
"Some believe that Austin could defensively catch in the major leagues right now," said Jaron Madison, the Padres scouting director.
"I have not seen at the amateur level that defensive prowess at any position, just not catcher," McLeod said of Hedges, who gets the ball to second in 1.8 seconds.
"He's got a great combination of quickness, athletic skill and understanding of the game. He's pretty special."
After catching Cory Luebke's bullpen session, Hedges took batting practice with the Padres and twice reached the seats in left.
"That was as impressive a batting practice session for a kid right out of high school as I've seen," said McLeod. "That was a bit of a surprise, a bonus. Great day."
Certainly a better day for Hedges than the afternoon in June when family, friends and the media gathered at his home expecting Austin would go high in the first round. But his strong commitment to UCLA and the fact that Scott Boras was his advisor conspired to drop Hedges in the draft.
Eight-one names had been called, including five by the Padres, when San Diego's pick came up in the second round.
McLeod placed a quick call to Padres CEO Jeff Moorad regarding Hedges.
"We had to have a conversation with ownership," recalled McLeod. "Still sitting there was the type of impact player we're looking to get. Impact player was the mantra.
"There had to be an agreement on making the commitment before we made the pick. The commitment was there."
The Padres spent $11.02 million on amateurs this season and were willing to go to almost $12 million to sign the only one of their top 26 picks who got away. But catcher Brett Austin turned down the Padres in favor of college.
Stauffer rebounds
As for the Padres of today, Stauffer allowed only one home run last night, holding the Marlins to that one run on five hits to lead the Padres to a fourth straight win over the Marlins this season.
The Padres three runs came in the first two innings off Javier Vazquez.
Jesus Guzman drove home Jason Bartlett and Cameron Maybin with a two-strike, two-run, opposite-field triple in the first. Hundley opened the second with his own triple to right and scored on a sacrifice fly by third baseman Logan Forsythe.
Stauffer, who allowed five home runs last Saturday night in Cincinnati and a franchise-record eight homers over his last two starts, worked 6 2/3 scoreless innings when John Buck homered.
Padres manager Bud Black said the difference in Stauffer was location.
"He left too many pitches out over the plate in Cincinnati," said Black. "There were more balls down in the zone, down and away. When he went inside, he hit his spot.
"Tim has to change speeds and hit spots."
"I was just trying to avoid the middle of the plate," said Stauffer.
"I was looking forward after that game (last Saturday) to get back on the mound as soon as possible knowing how that game finished. It wasn't what I knew I could do.
"I felt I pitched my kind of game tonight, throwing strikes and keeping the ball on the ground and keeping a good pace going."
The Marlins had the tying run on in the eighth when former Marlin Maybin made a diving catch of a sinking liner by Gaby Sanchez.
"I got a good read on it," said Maybin. "It's a play where they have two guys on. You've got to sell out. We needed that big play to stop that momentum they had going."


text:
Earlier this week, we heard from Craig on where the bar is set for the 2013 Cleveland Browns. Given that expectations and predictions are undoubtedly different, we here at WFNY provide you with what we feel will happen between today and the conclusion of the regular season. Do enjoy.
1. Fill in the blanks: Trent Richardson will play ___ games and finish with ____ yards and ____ total touchdowns.
Rick: Trent Richardson will play 15 games and finish with 1300 yards rushing and 16 total touchdowns. He has shown he is willing to play when hurt, and so despite getting banged around he plays the majority of the season. The Browns will ride him all year. He will raise the infamous yards per carry number to 4.1 this year.
Andrew: Trent Richardson will play 15 games and finish with 1,103 yards and 12 TD. I don't really know what to make of Richardson. Everyone seems to be pretty high on the guy, but I've never really seen anything that truly "wows" me about him. I think he's an average, serviceable NFL running back, and these numbers reflect that.
Craig: Trent Richardson will play all 16 games and finish with 1527 yards rushing and 14 total touchdowns. Trent is willing to play hurt. I think his level of hurt last season was odd for him. I expect a bounce-back kind of year health wise.
Kirk: Trent will miss, let's say two games (those nagging injuries are just going to happen), but he's still going to run for 1,000 yards and have double digit touchdowns. I'll go with 1,265 yards rushing, 325 yards receiving, and 14 total touchdowns (11 rushing).
TD: Trent Richardson will play 15 games, total 1,300 rushing yards and 13 touchdowns.
Jacob: Trent Richardson will play 14 games and finish with 1,100 yards and 13 total touchdowns. A better and more efficient season that his rookie campaign, but some durability issues continue to be a mild factor.
Scott: Trent Richardson will play 13 games, rush for just under 1,200 yards and 13 total touchdowns. The work load will make us wonder what could have been had he stayed healthy, but it will also force him to miss a few games in the second half. The guy is a truck and always gets hit more than once with each carry. Given the lack of depth behind him, I fear it may cost him a bit.
Ben: I'm gonna be super optimistic and say that Trent Richardson will play 16 games and finish with 1,200 yards and 16 total touchdowns. He's gonna be a beast the entire season and never ever get hurt. Ever. I do think he'll get loads of touches in cool, interesting situations near the goal line.
2. Now do the same for Brandon Weeden, but add a line for interceptions.
Rick: I'll go with all 16 games for Brandon Weeden. Let's say 3,600 yards, 18 touchdowns and 15 interceptions. Basically, just enough to make us all wonder in the off-season if he has done enough to keep the starting job or if the Browns will go looking for a new franchise QB.
Andrew: Brandon Weeden will play 16 games and finish with 3,580 yards, 17 TDs, and 16 INTs. I expect the Browns to be behind in a lot of games and Weeden will have to throw a lot. I don't really expect to see exponential growth, but I do think Weeden will be a little better than what we saw last year.
Craig: Brandon Weeden will play 14 games, throw for 3200 yards and throw 16 TDs and 14 interceptions. I really don't have any idea why I picked these numbers, but I think it's going to be another up and down season that will leave fans and the team wondering if he can be the guy. Ultimately this will mean that he isn't if you don't know after year two and the Browns will be looking for a QB this off-season. It won't be so bad that some will say he made progress.
Kirk: Brandon Weeden will miss one game at some point in the middle of the year, but he will throw for 3,655 yards passing, 20 touchdowns, and 15 interceptions. I think Weeden shows improvement and the more vertical attack promised leads to some more passing touchdowns. He's still going to have plenty of those head-scratching picks though, I fear.
TD: Weeden will play 15 games, and throw for 3800 passing yards and 18 TDs
Jacob: Brandon Weeden will play all 16 games, throw for 3,900 yards, 19 touchdowns and 16 interceptions. Again, a better season. The Browns will throw it more often and farther. Several of his passing TDs again will go to Richardson. His season keeps him in the conversation if the best QBs aren't available at the Browns' 2014 drafting spot.
Scott: Brandon Weeden will play 15 games, throw for 3,785 yards, 19 touchdowns and 16 interceptions. The Browns are going to air it out and take a few more chances than in years past. This will lead to a few punt-by-proxy passes, but will pad the yardage total and lead to an additional touchdown or two when these passes replace what would've been a dump-off.
Ben: Continuing the optimism, Brandon Weeden will play 16 games, throw for 3,700 yards with 20 TDs and 13 INTs. Norv's offense will do wonders for the 30 year old sophomore. He'll also totally stop staring down his receivers.
3. Fact or Fiction: Billy Cundiff will finish the season as a member of the Cleveland Browns.
Rick: I'm going to say fiction because I think that the Browns actually like Brandon Bogotay and will give him another shot sometime this season when he is healthy again.
Andrew: Fact? Projecting kickers is a new thing for post-1999 Browns fans. The Browns front office obviously doesn't put too much stock in the kicking position, so maybe it's dumb to think Cundiff will finish the season with the Browns, but we'll see.
Craig: Fact: Billy Cundiff will play well because he wants a chance at this job next year too.
Kirk: BIG fiction on this one. Cundiff's lack of distance is going to leave some points on the board, and I could see him falling into an inescapable funk at some point. He'll hold the job until the bye week, where they'll sign another young kicker to compete with Brandon Bogotay in 2014.
TD: Fiction – this kicker search has been botched from the get go. If Cundiff was good enough, wouldnt he be kicking for someone else?
Jacob: Fact. Billy Cundiff is an adequate mid-range kicker. Since he returned to the league in 2009, he's been better than the league average in accuracy within 49 yards. Fans will miss Phil Dawson still, but Cundiff will be adequate. He won't return in 2014 and the Browns will draft a late-round kicker. Finally.
Scott: Fact, but only due to pure trolling. Cundiff can hit the easy ones. He won't shorten the field in the way that Phil Dawson did, but it will also force the Browns to take chances for the red zone as opposed to just trying to get to the 35.
Ben: Fiction. One can't help but be uninspired by the Cundiff signing and. I'd be shocked if Billy was still their kicker at the end of the season.
4. The most surprising player will be…
Rick: The most surprising player? I'm going to go with Craig Robertson. Robertson's name has come up a number of times throughout camp as a player to watch. Ray Horton gets excited talking about him. He has a shot to be very good in this defense, and because of his speed he will be all over the field.
Andrew: The most surprising player will be Davone Bess. I think Weeden likes to fall back on safety nets a lot, and I think Bess will be his security blanket. I don't know that Bess will have a lot of yards or TDs, but I do think he will have a lot of receptions and be a steady presence in the Browns passing game.
Craig: The most surprising player will be Desmond Bryant. Maybe a big free agent shouldn't be, but because he's played so sparingly in the pre-season I don't think Browns fans have a flavor for how good he can be. I expect big things from him this year, and I think he'll surprise a lot of fans.
Kirk: I'm going to go with Craig Robertson as well. I expect him to fly under the radar and rack up a lot of tackles in the middle of this defense and not get out of position much at all.
TD: Jabaal Sheard. For some reason I have the feeling that he will really take to the 3-4 outside linebacker spot and thrive.
Jacob: Can I just pick Davone Bess? People often forget how reliable he has been for the Miami Dolphins. He's one of only 10 NFL players to catch 50+ balls in each of the last five seasons. He'll be a durable, steady and productive safety valve for Weeden. Great pick-up.
Scott: I too will go with Jabaal Sheard. He's getting overlooked due to the additions of Paul Kruger and Barkevious Mingo. I think his speed rush will be utilized even more than in the past few seasons. It may get to a point where we'll all ask ourselves why the Browns had not been running the 3-4 this whole time. Honorable mention: TJ Ward.
Ben: The most surprising player will be Buster Skrine. Maybe he'll surprise us by not being terrible. Eh?
5. The biggest disappointment (player) will be…
Rick: Let's get this out of the way. No matter who the kicker is, they will not live up to the gold standard in town. That shouldn't surprise us though. This said, I'm torn between two players. Paul Kruger is the big money man. He hasn't been a full time player in the NFL as of yet. I think there will be a bit of an adjustment. His weakness in the running game will be on display, but I think he isn't the biggest disappointment.
That will be Greg Little I'm afraid.
I know he has been working hard before, during and after practice. He looks better in drills. But during the preseason games and even during 11-on-11 drills he tends to fade into the background.
Andrew: The biggest disappointment will be Trent Richardson. I swear I'm not reverse jinxing the guy (or am I???), but I just don't see it. He still looks a little hesitant hitting the hole and I don't think his vision is the quickest. It just seems to take him a while to make up his mind what he wants to do, and that's a perilous trait for RBs to have.
Craig: The biggest disappointment will be Brandon Weeden. It might not be fair, but with all the advancements I think the rest of the team can make, it's going to feel a lot like Weeden is the one holding the team back as they improve on defense and also running the ball.
Kirk: With Davone Bess and Josh Gordon getting more looks, I could see Greg Little pouting a bit and having his production slip. I'm going to go with Barkevious Mingo. He's already got the quirky injury for Week 1, and I think Kruger and Sheard could hold down those starting spots, forcing him to fill in the cracks. I like his potential long-term, but it could be a little underwhelming on the stats sheet this year.
TD: Brandon Weeden – the Browns will be back shopping for a QB in the 2014 draft.
Jacob: Paul Kruger is the easy pick here. This signing reminds me a bit of Nick Swisher: All-Pro money for a solid yet unspectacular cog. I'll also go with Travis Benjamin, a speedy playmaker who won't suddenly develop into a go-to target as some fans desire. He's still an inconsistent youngster.
Scott: D'Qwell Jackson. He may be one of my favorite players on the team, but I think this defense will phase him out in terms of statistical totals. He'll be the leader this team continues to need, but between the edge rushers and the big bodies on the line, his impact will be a considerable decrease from what we've grown used to.
Ben: Brandon Weeden. I know this completely contradicts my answer to number 2, but here we are. I doubt we'll end the season feeling optimistic about Mr. Weeden.
6. The players who will represent the Browns in the Pro Bowl, if anyone, will be…
Rick: Joe Thomas. The voting is different this year, and it will be interesting to see how it plays out. Who am I kidding. Nobody cares.
Andrew: I'll stick with Thomas, but will add Paul Kruger and Joe Haden.
Craig: Joe Thomas and Joe Haden. It's Haden's time. He will take this new defense and increased QB pressure and do some remarkable things.
Kirk: Trent Richardson, Joe Haden, and Joe Thomas. I'm highly confident the Browns get more than one player.
TD: Joe Thomas on reputation alone. Im going to say Trent Richardson as well. I think he is going to be a monster this year.
Jacob: Joe Haden, Joe Thomas and Trent Richardson. The studs get their worthy due. Whether Richardson will be healthy enough to play, I'm uncertain. But he'll certainly receive the nod.
Scott: Joe Thomas, Trent Richardson and Joe Haden. I don't know if Richardson's games played will be a point of contention, but the NFC is the side loaded with the quality running backs (AP, Lynch, Morris…). Richardson can easily join Ray Rice, Stevan Ridley and maybe Jamal Charles. I'm struggling to see who else would make it at this point. Also, this is finally Joe Haden's time.
Ben: The players who will represent the Browns in the Pro Bowl, if anyone, will be Joe Thomas and Travis Benjamin.
7. The Browns record, when it's all said and done, will be ____. They will finish ___ in the AFC North.
Rick: The Browns record will be 7-9 and they will finish third in the division, above the Steelers.
Andrew: The Browns record will be 6-10. They will finish 4th in the AFC North. I do think that if some breaks go their way, the Browns can finish 8-8 or possibly even 9-7. But when do breaks ever go the way of the Browns? More likely, a couple injuries will hit and the depth issues with this roster will take their toll and wreck what could have been a promising season. I don't relish being a downer on this team, but I just haven't seen enough progress to make me believe they can really win more games than they lose.
Craig: The Browns record will be 9-7 and finish second in the AFC North. The Ravens are going to take a step back and so are the Steelers. (Yes, this is wishful thinking. I hate making predictions, and here you've forced me to make a bunch of them, so this last one's for me.)
Kirk: The Browns will go 8-8 and finish third in the AFC North ahead of the Steelers. They'll grab a win against each of the AFC North teams, gaining traction for the future battles with these three. This team is so much better on paper than the 5-11 team that lost a lot of hard luck games, so I find it hard to believe that they can't/won't win 3 more games (at bare minimum two more). Still, as much sunshine as I like to exude, I just can't see this team doing any better than 8-8 either. They would have to get some truly unforeseen contributions and stay remarkably healthy to go 9-7 (or better).
TD: 6-10, last. They will be more competitive, but this secondary problem is not going away and could be a real problem is a league that has become so pass happy.
Jacob: I'll go with 7-9 and tied for third. Cincinnati wins the AFC North followed by Baltimore at 8-8. Then, Pittsburgh and the Browns split the season series and tie for last.
Scott: I want to say 7-9 so badly, but I'm leaning toward 6-10. I hope I'm wrong, but between a lack of depth and the fact that Buster Skrine is going to log heavy snap totals, I just don't know if single-digit loss totals are in the cards. They'll once again bring home fourth in the AFC North, but it'll be a lot closer than in years past.
Ben: The Browns record, when it's all said and done, will be 6-10 They will finish 4th in the AFC North. Would be thrilled to be wrong.


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|592 sq. ft.
|Property type
|Minimum Stay
|3 - 4 nights
APARTMENT 2 (for 2 persons) This apartment is available from end March 2012, bookings are already possible. It has a nostalgic feel with real Portuguese oriental bamboo ceiling details such as hand-blown glass doors and windows and ceramic tiles on the floors, the bathroom has hand-painted Portuguese tiles, the entrance is a small staircase with three steps, you will enter the hall that house divided into sleeping and living area (55 m2) with one double bedroom / bathroom-toilet / beautiful living room. open real wood kitchen with all amenities such as oven and dishwasher, microwave and refrigerator / freezer combo nation. The apartment has air conditioning, heating and warm air heating. From your balcony overlooking the garden and pool located in the surrounding countryside. This apartment has the most sunshine on the balcony, the house he is also great for winter long term, this special prices
The Villa
Casa Sereno is lying on a two thousand square metres land in a very natural and woodrich surrounding with planty of trees and plants. If you're interested in a real quiet location, which is nevertheless lying near all tourist sights and entertainmentpossibilities, then we're sure that Casa Sereno is just what you're looking for. A select place of sitting in the garden or lying lazely in a hammock beneath almond trees, or painting o none of the many idyllic places but also to walk to the beach or along the coast. The villa has a nostalgic display wih bamboo ceilings, round handblown windows in a wooden frame, spacious bathrooms, good beds and smartly decorated living areas as well as plenty of room for wardrobes. Care is also taken for Floor-heating in the wintermonths. Last but not least, each appartment is in the possession of a TV with all kinds of channels and WIFI for free use. The location is situated on a 40 minutes drive only from the airport of Faro. A clear routdescription will sent to you before you come. Nearly everything is really lying within 5 minutes drive, such as three beaches, supermarkets, pleasent places such as Carvoeiro, golf and tenniscourts. Casa Sereno has beautiful appartments for two or four persons. All appartments have their own entrance and the terraces and the balconies having view on the garden, the swimmingpool and the beautiful surroundings of the Vale del Rei.
APPARTMENT COSY :( suitable for two persons but in combination with the studio it is for four persons)
Has a nostalgic display wth real Portugal details. It is situated on the First Floor with an own entrance. It has a seperated bedroom, a spacious bathroom, a stylish livingroom with TV., an open kitchen, supplied with all comfort such as an oven, a dishwasher and a combination for cooling and freezing. The appartment is supplied with an airco, free WIFI, and underfloorheating and a woodstove. From your balcony you have a lovely view on the garden and the swimmingpool with green all around. (55m2)
APPARTMENT ZEN : (suited for two persons but in combination with the studio also for four persons)
Has a Oriental display with charming details. It is situated on the First Floor and has a balcony as well its own terrace. You will have view to the garden and the swimmingpool and the green surrounding. It has a seperated bedroom, a spacious bathroom, a nice livingroom with an open kitchen supplied with all possible comfort such as a dishwasher an oven and a cool and freeze combination. Also TV., airco and free WIFI. (55m2)
APPARTMENT BEACH : (suitable for two or four persons with a luxury sofa or in combination with the studio )
Has a modern but attractive style and has a big sleepingroom with a sink and a bathroom with a walk in shower. Also a big livingroom nice decorated with TV and airco/hot air heating and free WIFI and a kitchen with an oven, dishwasher, and a cool and freeze combination. This appartment is lying on the groundfloor and has a large terrace looking out on the garden with swimmingpool and the green surrounding.
STUDIO BELEZA : is suitable for two persons. It can be rented in combination with the other appartments and also separately with breakfast. It has a sleepingroom and a separately bathroom. Also two chairs and a table. It has its own terrace with a view on the garden and swimmingpool. The studio is on the groundfloor.
Casa Sereno is a place where guests are keen on there rest, therefor Casa Sereno is less suitable for children younger than fifteen years.
It is also possible to rent all the appartments as a group till max. 10 persons. Ask about the conditions.
We, Kees Jetten and Karin van de Burgt, like to welcome you at Casa Sereno. Our motto is "live your dreams" and that is what we already experienced by immigrating to this part of Algarve in Portugal. Our intension is to care for a nice and clean apartment with comfortable beds and a fully equipped kitchen. Our guests can also enjoy a gorgeous pool, surrounded by a sub-tropical garden with plenty of sunbeds. In the atmosphere of tranquility, hospitality and privacy we are sure that you will feel at home in our resort. By arrival we will welcome you and after a short explanation of your apartment, you can start enjoying your holiday. We understand that our guests like their privacy and of course we will respect this. However we can image that you like to get some information about the environment and the available facilities. Of course we are always prepared to answer your questions in such a case. From june onwards a four course dinner will be cooked as well that you can enjoy in a relaxed atmosphere together with other guests in a special ambiance. In the Netherlands Kees and myself were busy in the rental business and I design interiours for houses and gardens. For rental purposes we also completely refurbished an old Austria house and rente dit for many years. And now in Portugal where we would like to welcome you in the confidence that you will have an unforgetable holiday.
The Algarve is one of the best kept secrets of Europe. See also the promotionpicture on our site. East of Faro, the coastal region consist of unusual lagoons and kilometres long small Sandy islands. West of Faro you find a chain of small beaches, surrounded by rugged cliffs and caves. In the sparsely, populated inland it looks as if the time has stand still and it is here that the old Portugalsphere still revives. You are surrounded by the peace and quiet, delicious smells and a beautiful nature; pines, eucalyptus trees, wild flowers,lavender and beautiful flowering and smelling almond trees in january and february. The Algarvian coast and the inland are an excellent walking area in all seasons. They treat the walkers to imposing cliffs, spledid viewpoints, picturesque, small villages and surprising nature reserves.
NATURE PARKS : (see www.portugalportal.nl)
1. Serra de Monchique : is the paradise for walkers in the west part of Algarve, immense peace, wealthy subtropical vegetation, fertile terraces and green valleys full of wild flowers such as mimosa, cork oaks, etc. On the highest summit Foia (905 mtrs) you can enjoy a magnificent look out. Monchique is also a pleasent small village with narrow alleys, brightly coloured houses and a authentic relaxed atmosphere.
2. Lagos dos Salvados is lying in the neighbourhood of our villa. It is a lagoon with brackish water, protected by a row of dunes against the Atlantic Ocean. A nice footpath has been constructed with a wooden platform so that you can easily walk through and back along the beach. It is the only breeding place of cattle egrets spoonbills, flamingos and white egrets.
3. Ria de Alvor : walkers as well as nature and birdwatchers can indulge themselves here. It is the restfeeding place from migrating wader as the caspian terns, plovers, flamingos and black tailed goodwits. The nature reserve can be explored from the village Alvor by making a nice walk partly along the lagoon and partly along the beach, thereby making a good use of the wooden stepstones. It is also possible to rent canoes to cross the lagoon. There is a varied walkingtour from 8 kilometres as well through the area from the original small raiwaystation from the Mexilhoeira Grande.
At only a few minutes driving there are beautiful beaches to find.
1. Praia Marinha ; this beach has been explained to one of the most beautiful beaches of Europe. Excellent rockformations, a wooden staircase leading to it and followed by a fine walk along the coast.
2. Praia Albandeiras an excellent enclosed beach with a lovely small pizzeria.
3. Praia Benagil with small fishingboats, nice small restaurants around the beach and a steep slope. From here you can also make a reservation for your boattrip
4. Praia Carvoeiro is a beach in the centre of an old touristic fishing village with nice, small restaurants, souvenirshops and many more.
HORSERIDING : In Bensafrim, a small village 6 kilometres before Lagos you'll find two maneges which offers offside rides. (www.herdade-do-castanheiro.de and www.qpahorseriding.com )
SAILING : To look at the sea with his beautiful cost and caves from the shoreline is very much rewarding. You can reserve a boattrip from Praia Benagil, right near the villa, as well as from Praia Carvoeiro. This is a most rewarding experience. What is also worth while is a trip with a pirate boat from Portimao. Very attractive and various tours with Music, canon and drinks, etc. (www.santabernarda.com) On the website www.natura-algarve.com you can find al kind of trips with picnic and all kind of trips on land.
SPOTTING DELPHINS AND WHALES : By means of email@example.com you can book for making a trip to watch dolphins
SURFING : by Praia Grande surfinglessons can be booked by Kalu. A beachclub with Dutch owners. Also canoeing from here is possible and further on in Lagos. ( (www.algarvewatersport.com )
BUGGY-SAFARITOUR : a tour through the Algarve you can book on www.bulldogbuggies.com it starts in Silves about ten minutes from the villa.
TENNIS : In Carvoeiro you can find the Carvoeiro Tennisclub with twelve illuminated tenniscourts, fitness and swimmingpool (www.tenniscarvoeiro.com)
GOLF : The Algarve is a paradise for golfplayers. There are 29 courses between Faro and Sagres, all within a radius of 40 kilometres. Close to the villa you'll find three of these, namely Petana Golfresort in Carvoeiro with two 18 holes courses ; the Pinta and the Gramacho. (www.petanagolf.com) and also in Carvoeiro the course Vale de Milho; a nice 9 holes course (www.valedemilhogolf.com)
Shoppingmall : there are two of them in close vicinity. A shoppingmall in Guia by Albufeira and the shoppingmall Jumbo in Portimao with a lot of chains such as H&M, Zara, Primark, Pull and Bear, but there are also many Potuguese shops. At the height of the season the shoppingmalls are open till midnight and in the lower season till eleven in the evening.
De huurprijzen zijn all-in en gelden voor twee personen. Bij een verblijf tot 4 nachten geldt een schoonmaak toeslag van € 35,-. Kortere verblijven zijn ook in de zomermaanden mogelijk indien ze als beschikbare dagen vallen tussen twee andere boekingen.
Voor het bij plaatsen van een baby-bed wordt € 15,- per nacht berekend. U kunt ook Beleza bij huren voor 2 personen. Met eigen douche en toilet.
Het is mogelijk om direct een auto te boeken tegen een scherpe prijs die voor u klaar staat op het vliegveld van Faro of op locatie. Vooral gedurende het hoogseizoen zijn de huurauto's schaars waardoor het aan te raden is dit vroegtijdig te regelen. Wij koken één keer per week een viergangen dinner (juni t/m september).
We werden zeer gastvrij ontvangen door Kees en Karin. Prachtige locatie, mooie tuin en in de appartementen ontbreekt werkelijk niets. Supermarkt, restaurants en strand binnen 10 minuten bereikbaar. Je komt er helemaal tot rust.
Wir waren 10 Tage dort – und es war großartig. Karin und Kees sind fantastische, sehr liebe Gastgeber. Unser Apartement war groß (wir waren zu zweit) und geschmackvoll eingerichtet. Die Küche war sehr gut ausgestattet – uns fehlte es an nichts. Und in nur 5-10 Autominuten ist man an den schönsten Stränden! Jederzeit wieder. Liebe Grüße von Susanne & Tom


text:
Dana Loesch sat down for an interview with TheBlaze ahead of the premiere of her new show "Dana" on TheBlaze TV at 5:00 p.m. on Friday, breaking down what the show will be about, what keeps her motivated, and the unexpected thing she does when she takes a break from current events.
More than anything, Loesch says she just wants to "have fun" with the program, and show people that "politics can be fun."
"It's punk rock conservatism. I want to have fun with it. I want to be 'fist in the air' and have a good time," she said with a smile. "You can have a good time and kick some butt – they're not mutually exclusive."
Loesch explained that one of the reasons she is so passionate about politics and current events is because of how much they have impacted her personal life. Ten years ago, she said, she was a feminist whose entire identity was "liberal first."
"Everything else, from being a Christian, a mother, a daughter, a friend everything else came second," she said.
But that all changed when Loesch became pregnant with her first child — a boy. She described how she had a "really jolting moment" in labor, when she realized that everything she had been advocating was "absolutely detrimental" to everything she needed to do as a mother.
When Loesch changed her beliefs, she said, a lot of people, from professors to friends to family, turned their back on her.
The newest Blaze TV host said she sees a lot of women where she was ten years ago, and wants to tell them: "don't be scammed."
Loesch is on the receiving end of what seems like a constant barrage of hateful messages and death threats on social media. Though she loves her job and described it as "Disneyland" every day, that has an effect on even the strongest of people.
When asked how she deals with it, Loesch promptly responded that like "any good capitalist," she "monetizes" the hate, reading the messages on-air for money and then donating the proceeds to a conservative issue, making it "work for good."
But when she really needs a break, Loesch admitted, she knits. "It's like mental yoga, I swear…" the fiery personality said with a laugh.
More than anything, Loesch said her faith that keeps her strong in what she does.
"I really believe if you in any fight are on God's side, that's pretty much it," she said. "My faith, my family, my friends – that's where I get my strength."
Looking forward, Loesch said she is confident that TheBlaze is "the future of media."
"It's a triple threat – you have radio, you have television, you have the web and print," she remarked. "So I think more industries, more outlets are going to be following the trail that has been set by this company."
See video from the interview, below:
Other Must-Read Stories:
- Is That Dana Loesch…With a Shotgun in TheBlaze TV's Dallas Studios?
- The Major Media Personality Who's Joining TheBlaze
- Dana Loesch Shares Incredible Story Behind Why She Rejected Liberalism After Getting Pregnant as a 'Broke, Unwed Student'
- Watch Dana Loesch Take the Obama Administration to Task Over IRS Scandal
- Dana Loesch Eviscerates Zimmerman Protesters Who Have Said Nothing for Victims in 'Utopian Dream' of Chicago


text:
Trouble perfume for Women by Boucheron
8.5 out of 10 based on 8 ratings
|Design House
|Fragrance Gender
|Women's Fragrance
|Year Introduced
|Available Types
|Jacques Cavallier
|Bottle Designer
|Scent Classification
|Oriental Floral
|Fragrance Notes
Popularity Total Hits: 29307
Voting Results
Scent Sillage: soft
based on 6 users opinions
Scent Longevity: 1-3 hours
based on 6 users opinions
Season: summer
based on 6 users opinions
Audience: any age
based on 6 users opinions
Occasion: day
based on 6 users opinions
Trouble Boucheron - Description
Fragrance Trouble perfume for Women by Boucheron was introduced in 2004. Boucheron Trouble is classified as Oriental Floral fragrance. Scent notes of Trouble Boucheron include top notes of lemon, dyer's broom, middle notes of jasmine and base notes of amber, vanilla, cedar wood. Boucheron Trouble fragrance composition is a creation of Jacques Cavallier.
Trouble perfume for Women by Boucheron 8.5 out of 10 based on 8 ratings and 6 user reviews. In stock From $52.00 to $52.00 based on 1+ offers.
Trouble Boucheron - Full Story
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Trouble Boucheron - User Opinions and Reviews
Date Added: 08/02/2016The person above who said ...rubbish this is been around for 20 years, is thinking about a Revlon fragrance, called trouble.I believe it was rough on, it was definitely not department store although it may have been at the time. This indeed was launched into thousand four as I was part of the launch partnering with Sharon I work for Nordstrom I believe it was rough on, it was definitely not department store although it may have been at the time. This indeed was launched in 2004, as I was involved in the launch. I adore this fragrance!!by Mel
Date Added: 27/01/2015Boucheron Trouble was a wonderful discovery i made many years ago. The beautiful feminine sexy aroma swept me off my feet the moment i first tried it and since then it has become my signature special occasion aroma. It has a really powdery sweet sensation with soft flowers zesty citrus outlines and a sexy wood touched dry down. Lasting power manages a good ten hours on my skin while projection is heavy and needs careful application.by Carrie
Date Added: 26/01/2015What a load of rubbish that it was first on the scene on 2004 - my daughter is using my Trouble perfume from around 20 years ago. Getting rave reviews at work etc. My husband bought it for me many years ago and, because it was kept in a cupboard, it's great still. Where do you get the 2004 from??? I also used to have a Trouble candle many years ago. xxby marion
Total User Opinions: 6
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