the increased prevalence of obesity and obesity - associated complications continues to be a major global health issue . high - fat ( hf ) , caloric - dense diets , sedentary lifestyles , increased urbanization and psychosocial stress are the most common contributing factors . obesity itself predisposes one to other diseases such as type 2 diabetes mellitus , hypertension , dyslipidemia , metabolic syndrome ( mets ) , atherosclerosis , degenerative joint disorders and cancer . the prevalence of mets increases with the severity of obesity and reaches 50% in morbidly obese youngsters . effective treatment with better prognosis can be achieved if we have a comprehensive understanding of the pathogenesis of the metabolic disorder . most studies so far focus on relating aberrant gene expression in the liver and adipose tissues to obesity , while less correlation is made between pathophysiological changes in the gut and obesity . in actual fact , emerging evidence have suggested that intestinal inflammation occurs during the development of obesity . inflammation in obese patients corresponds with increased plasma levels of c - reactive protein , tumor necrosis factor ( tnf)- , interleukin ( il)-6 , monocyte chemotactic protein-1 , il-8 , leptin and osteopontin . , a significant positive correlation between body mass index z - score and c - reactive protein may lead to obesity - related complications . obesity and diabetes alter the glucose - stimulated gut - to - hypothalamic nitric oxide signaling pathway . the disrupted enteric glucose detection is associated with a significant increase in inflammatory , oxidative / nitric oxide and endoplasmic reticulum stress gene expression . signaling mechanisms reported to promote inflammation have also been found to be initiated and/or mediated by luminal lipid and gut microbiota . these observations have collectively suggested the importance of preserving gut function , and a greater understanding of the pathological state of the gut may be useful in finding new strategy to treat and to prevent obesity . the review will first present different mechanisms in the gut that promote directly or mediate the development of obesity under the influence of hf - diet . these include descriptions of a number of established and hypothetical gut lipid - sensing systems that are present in the body to regulate glucose production . this is followed by addressing the impact of lipid - induced inflammation , and reporting data that linked these pathological changes to obesity . the review will then discuss the role of microbiota , which has been associated with inflammation - driven insulin resistance . this topic is of particular interest because the presence of antioxidants in the gut appears to be less appreciated compared with its other physiological functions such as metabolism and absorption . the second part of this review will summarize potential treatments proposed to manage these pathophysiological changes , namely to point out the effectiveness and feasibility of these therapies , and the use of dietary antioxidants as a probable direction for future treatment . this section aimed to provide evidence about the presence of several lipid - sensing systems in the body , which has been linked to obesity and mets development . among the different types of stimulus , cholecystokinin ( cck ) is the most established peptide hormone that initiates a gut  brain  liver neuronal mechanism . lipids in the lumen stimulate the release of cck from i cells that line the mucosa of the duodenum , which then binds to cck - a receptor in the gastrointestinal system . the impact of cck release was demonstrated in an in vivo experiment using cck-8 , which is an active form of cck . by cannulating the gut and using pancreatic clamp techniques the effect was reversed when cck - a receptor inhibitor mk-329 was co - administered with cck-8 . the importance of cck - a receptor in regulating glucose production is further evidenced when receptor - deficient rats become glucose intolerant , obese and eventually diabetic . briefly , hepatic vagotomy , inhibition of gut vagal afferent neurons by anesthetic tetracaine administered into the duodenum , and inhibition of glutamatergic neurotransmission in the nucleus of the solitary tract by direct infusion of n - methyl--aspartate receptor inhibitor mk-801 have all been shown to negate the ability of cck-8 to lower glucose production . clearly , the nucleus of the solitary tract is relaying a signal from the intestine to the liver for the effect on glucose production . stimulation of this network is independent of changes in food intake , but a mere 3 days of hf feeding attenuates this lipid - sensing mechanism . besides cck , lipid was suggested to induce the production of oleoylethanolamide ( oea ) in the mucosal layer of the duodenum and jejunum . oea is then taken up by cd36 , a membrane glycoprotein , which may act both as a receptor and a transporter . it is reported recently that lipid - induced oea mobilization in the gut is controlled by sympathetic nervous system . surgical removal of the sympathetic innervation and pharmacological blockade of 2-adrenergic receptor abolish the effect of oea . taken together , if this hypothetical model is correct , oea is hence an endogenous proliferator - activated receptor- ligand where its synthesis can be modulated by pharmacological intervention . the effect of hf on this mechanism has not been demonstrated but hf alone is known to suppress proliferator - activated receptor-. in another study , when lipids are infused into the duodenal segment , the elevated long - chain fatty acyl - coenzyme a ( lcfa - coa ) inhibits hepatic glucose production . with gut and hepatic vagotomy diminishing this effect support the existence of another gut  brain carnitine palmitoyltransferase-1 ( cpt1 ) , located in the outer mitochondrial membrane , is regulating entry of lcfa - coa into the organelle , where lcfa - coa undergoes -oxidation . however , upregulation of intestinal cpt1 as a result of hf feeding may not be helpful because the signaling effect of lcfa - coa is disrupted in hf - diet - induced insulin - resistant and obese rodents . as for cpt1 expressed in the hypothalamus , an inhibition on the enzyme decreases food intake and glucose production . nonetheless , the link between intestinal lcfa - coa and hypothalamic cpt1 in the regulation of glucose homeostasis is currently unclear . n - acylphosphatidylethanolamine ( nape ) is a class of phospholipids readily synthesized by small intestinal tissues when lipid is consumed . circulatory nape at physiological doses reduces food intake in a dose - dependent manner . via the method of radioactive labeling , nape was found capable of entering the central nervous system and accumulated in the hypothalamus . nape acts through the central nervous system because its hypophagia effect was observed in vagotomized rats . in the intestine , nape is hydrolyzed to n - acylethanolamines by enzyme nape - specific phospholipase d. however , animals fed with hf - diet containing variable percentages of fat have n - acylethanolamines decrease in a dose- and time - dependent manner . , hf - diet attenuates the secretion of nape and n - acylethanolamines , which are supposed to be a feedback response to the presence of intestinal lipid . different from other sensing molecules , which are lipids , acyl coa - monoacylglycerol acyltransferase-2 ( mgat2 ) is an interesting enzyme that controls obesity development . it is highly expressed in the proximal region of the small intestine , and is responsible for about 75% of triacylglycerol synthesis in the intestine . conversely , mgat2-deficient mice are protected from obesity , hyperinsulinemia , glucose intolerance , hypercholesterolemia and hepatic steatosis . although the underlying mechanism leading to these effects are poorly understood , specific identification of this enzyme with its relevance to mets parameter is an important finding for obesity treatment . in summary , sufficient data have demonstrated that central nervous system bridges the function of two visceral organs in the regulation of blood glucose level . despite the fact that extrapolating these animal data to human condition is not straightforward , it is only through animal study that one can understand the mechanisms involved and identify important targets for the development of more effective therapies for obesity . liver mechanisms shows the complexity of the lipid - sensing system , which may have potentially increased the difficulty of managing obesity and obesity - related complications . gastrointestinal tract ( git ) is the most common route of food and drug administration , which means git is generally the first organ to be exposed to attacks by pro - oxidants from the diet , phagocytes activated by diet - derived bacteria and toxins , and the effects of hf - diet . hf - diet in particular , is reported to activate mast cells and toll - like receptors ( tlrs ) . in balb / c mice , an in situ duodenal administration of butter rich in saturated fat cytokine at low level is beneficial as it modulates barrier functions and protects the epithelial layer . however , various lcfas micelles ( range between 10 and 50   ) administered to lymphocytes ( 200  l , 4  10 per well ) have dose - dependently inhibited the production of interferon-. incubation of lcfas ( 0.01 to 0.1  m ) with epithelial cells increases the secretion of growth - regulated oncogene / cytokine - induced neutrophil chemoattractant-1 and il-6 , also in a dose - dependent manner . intraduodenal infusion of polyunsaturated fatty acid - rich lipid emulsion activates intestinal mucosal mast cells , causing the release of histamine , rat mast cell protease - ii and prostaglandin d2 . the physiological significance of the activation of mast cells during fat absorption is not known . it is possible that by increasing lymph flow and vascular permeability , histamine facilitates the passage of chylomicrons particles through the lamina propria . rat mast cell protease - ii may increase epithelial permeability by suppressing the expression of tight junction - associated proteins zonula occludens-1 and occludin . moreover , rat mast cell protease - ii is specific for mucosal mast cells and selectively attacks type iv collagen in the basement membranes . of note bacterial endotoxin or lipopolysaccharide ( lps ) is present in large quantity in the gut . that a small amount of lps may co - transit with dietary fat from the gut postprandially , and activates leukocyte and endothelial cells . subcutaneous lps infusion induces several features of mets in mice and triggers the release of inflammatory factors . in addition , obese - prone rats treated with hf - diet exhibit an upregulation of tlr4 in the gut wall and a decrease in the intestinal alkaline phosphatase activity . the intestinal alkaline phosphatase is a duodenal brush - border enzyme that detoxifies lps . binding of lps and non - esterified free fatty acids to tlr4 initiates the secretion of various pro - inflammatory cytokines from the macrophages , adipocytes and liver . conversely , tlr4-deficient mice are partially protected from non - esterified free fatty acid - induced insulin resistance . similarly , cd14 mutant mice challenged with a hf - diet or given an lps treatment , resisted cytokine production , hypertriglyceridemia , insulin resistance , obesity and visceral adiposity . with cd14 being a co - receptor of tlr4 suggests the presence of two binding sites on this receptor complex that controls insulin sensitivity as well as the development of mets parameters . overall , luminal lipid by direct action on the enterocytes and through activation of mast cells , causes the release of cytokines . there is sufficient evidence to show that lipid induces inflammation in the course of obesity development . further to this , ding et al . are convinced that intestinal inflammation precedes and correlates with diet - induced obesity , adiposity and insulin resistance . they suggest that hf interact with gut microbiota to trigger the expression of tnf- and nuclear factor - kappab . the absence of microbiota in germ - free ( gf ) mice has blunted upregulation of these biomarkers , which are primary indicators of inflammation . with regard to this , our understanding on the onset of inflammation is not complete without mentioning the role and the effect of gut microbiota . already been reported almost a decade ago that although food consumption was significantly lesser , conventionally raised specific - pathogen free ( conv ) mice have a 40% higher total body fat content than the gf mice . interestingly , gf mice developed a 60% increase in their total body fat when being colonized with microbiota harvested from the cecums of conv mice . the resistance of gf mice to diet - induced obesity is due mainly to the animal having a different genetic make up for lipid processing in the intestine . microbiota via carbohydrate response element - binding protein enhances uptake of monosaccharides and hepatic triglycerides production . through the suppression of angiopoietin - like protein 4 ( fiaf ) , which is a lipoprotein lipase inhibitor , microbiota promotes incorporation of triglycerides into the adipocytes . on the contrary , fiaf is highly expressed in gf mice . fiaf induces peroxisomal proliferator - activated receptor coactivator-1 in the gastrocnemius muscle whereby this nuclear receptor increases mitochondrial fatty acid oxidation . high levels of phosphorylated amp - activated protein kinase in gf mice also promote fatty acid oxidation in the skeletal muscle and insulin sensitivity . furthermore , microbiota increases energy and lipid metabolism by upregulating genes involved in the tricarboxylic acid cycle and pyruvate metabolism in the liver . by acting via g protein - coupled receptor 41 ( gpr41 ) gpr41-deficient mice demonstrate a decrease in peptide yy ( pyy ) secretion , and reductions in intestinal absorption and delivery of short - chain fatty acids , as well as hepatic lipogenesis . including gpr41 , several other gpr expressed on enteroendocrine cells activation of gpr41 and gpr43 by short - chain fatty acids leads to the release of pyy , whereas gpr40 and gpr120 via lcfa as ligand of these receptors , have been implicated in cck release . although these recent data shed light on the mechanism responsible for gut hormone release , precise mechanisms by which fat is sensed , and subsequent signaling pathways that lead to changes in gi function , energy intake , hence body weight , are still not well understood . microbiota is shaped by an innate immune system that helps to defend the host against infection by pathogenic microbes . tlr5 , a component of the system and a transmembrane protein , is highly expressed on the intestinal mucosa . tlr5-deficient ( t5ko ) mice have significantly higher body masses than age - matched wild - type mice , exhibited sign of hyperphagia , have high production of pro - inflammatory cytokines in the adipose tissue , and developed other hallmark features of mets . a broad - spectrum of antibiotics introduced to t5ko mice at the time of weaning for a period of 12 weeks , attenuated hf - diet - exaggerated mets development . when t5ko microbiota is transplanted into the intestine of wild - type gf mice , the latter developed t5ko mets phenotype . these data indicate that a change in microbiota composition increases the risk of metabolic disorder . recently , serino et al . reported that metabolic adaptation to hf - diet is associated with a change in metabolic phenotype - specific gut microbiota , which is independent of genetic factor and diet . effects exerted by this signature microbiota , such as increased production of adipokine , adipose cell size and stroma vascular fraction cell number , are facilitated by increased paracellular permeability in the ileum and cecum of the hf - fed mice . however , data describing the effect of microbiota - brain axis on feeding behavior is still lacking , thus will not be discussed in this review . figure 1 highlights the effects of hf - diet , by which hf through multiple mechanisms , disrupts glucose homeostasis and mediates the development of obesity . one of the components of the gut that is frequently neglected in most reviews is gut antioxidants . as git is the first organ exposed to exogenous compound , microorganism and free radicals , other than the immune system , git is expected to possess high levels of endogenous antioxidants , which act to protect itself against free radicals and to filter out pro - oxidants from entering the circulation . with many studies reporting the effectiveness and the use of natural antioxidants to prevent and ameliorate obesity , it might be worthy to better understand and explore the role of gut antioxidants in this context . enterochromaffin cells of the mucosal epithelium are the major source of melatonin in the body . melatonin is a powerful antioxidant , a free radical scavenger , and probably the only endogenous gut antioxidant having well - defined properties . its ability to scavenge a myriad of radical species protects git against lipid peroxidation , oxidative dna and protein damages . melatonin has anti - aging , anti - carcinogenic and antitumor effects , and it enhances immune function . majority of these effects is mediated through mt1 receptor . theoretically , gastroduodenal mucosal layer is protected from acid - induced injury by the existing protective mechanism , namely bicarbonate and mucus secreted by the superficial epithelial cells . intracerebroventricular infusion of the 1-selective adrenoceptor agonist , phenylephrine , causes significant release of melatonin and bicarbonate from the duodenal mucosa . mt2 inhibition by luzindole ( 600  nmol / kg , intravenous ) , blocks bicarbonate but not melatonin secretion . this suggests that melatonin - stimulated bicarbonate secretion is mediated via the central nervous system . melatonin injection ( 10  mg / kg , intraperitoneal ) before physical and psychological stress protects the animals from mucosal degeneration , inflammatory cell infiltration and generation of free radicals in the gastrointestinal tissues . daily injection of melatonin ( 0.5  mg / kg , subcutaneous ) for 12 days also reverses body weight gain and food intake , which were significantly higher in pinealectomy than sham - operated rats . these favorable outcomes have important impact because psychosocial stress has increasingly been linked to inflammation and obesity . apart from melatonin and possibly many other less characterized endogenous antioxidants , gut may gain protection from dietary antioxidants . they have low bioavailability , with high concentration being observed in the stomach and intestinal lumen . the low bioavailability of flavonoids has long been known to be attributed to the compounds hydrophilicity . non - flavonoids such as vitamin e and carotenoids , and water - soluble antioxidants are also found at high concentration in the mucosa of the avian species . flavonoids and other phenolic compounds exert direct protective effects on git by scavenging reactive oxygen and the chlorine species . a wide range of treatments has been proposed to correct pathophysiological changes in the gut as a result of hf consumption . there are several approaches to overcome suppression of the gut  brain  liver sensing mechanism . these include upregulation of cck - a receptor expression , using a cck - a receptor agonist and modulate signaling proteins that act along the cck / cck - a receptor g protein - coupled signaling pathway . with regard to the oea - mediated local signaling pathway , there have been suggestions to increase the expression of cd36 and magnify oea , either from diet or through inhibition of oea degradation . alternatively , central or intestinal inhibition of cpt1 by genetic and biochemical modification , and increases dietary lcfa - coa . however , since the concept of lipid - sensing - regulated glucose production is relatively new , more study is required to demonstrate the effectiveness and practicality of these therapies . study should establish both the toxicity and pharmacokinetics profiles of new drugs that act on the neuronal axis . other studies such as verification of whether regulating a singular sensing pathway is more ideal or combining pathways will give an additive effect ; and comparing the efficacy between established treatments and regulation of lipid - sensing system remained to be explored . one of the main consequence of hf ingestion is causing significant disruption to the tight junction , possibly through activation of mast cells . in this regard they improve the distribution of occludin and zonula occludens-1 , and promote normalization of the endocannabinoid system responsiveness in the gut , thereby reduce gut permeability , metabolic endotoxemia and fat mass development . they avert the re - arrangement of tight junction proteins , upregulate the expression of claudins and occludins , and normalize the barrier function . however , both prebiotics and probiotics do not improve metabolic profiles in obese rodents . mast cells stabilizers disodium cromoglycate and ketotifen have been shown to reduce body weight gain and abdominal fat mass in diet - induced obese mice . these animals also have reduced inflammatory cytokines , chemokines and proteases in the serum and white adipose tissues , and have shown better glucose tolerance and insulin sensitivity . bifidobacteria are beneficial to the gut because they reduce intestinal lps and improve mucosal barrier function . young male rats treated for 10 weeks with diets containing 10 and 20% of prebiotic inulin : oligofructose ( w / w ) had a dose - dependent increase in bifidobacterium spp . and lactobacillus spp . the effects of prebiotics on improving gut barrier function and inflammation are partly through upregulation of glp2 , thus suggesting the potential use of glp2 to prevent metabolic endotoxemia and metabolic disorders . co - secretion of glp1 and glp2 is implicated to decrease circulatory lps and cytokines . on the other hand the subsequent effects include restoration of intestinal permeability , lowering of plasma lps , attenuation of adipocyte inflammation and oxidative stress , and improvement in mets parameters . despite these therapies , it is necessary to note that the composition of the gut microbiome is dynamic and adaptable . to achieve high efficacy there are suggestions that antibiotics affect epithelial integrity , and widespread use of antibiotics in early life may cause obesity . moreover , as to whether long - term ingestion of a broad spectrum of antibiotics will lead to other disorders is still not known . hence , it is probably preferable to specifically target on proteins that regulate the development of obesity . for example , fiaf and proliferator - activated receptor coactivator-1 to modulate fat storage ; gpr41 ( ref . 44 ) , tlr4 , cd14 ( refs 37,39 ) and tlr5 ( ref . this enzyme converts inactive cortisone and 11-dehydrocorticosterone to the active cortisol in human and corticosterone in rats , respectively . in order to understand the mechanism of excessive glucocorticoids - induced growth of visceral fat , matsuzaki et al . these transgenic mice have increased corticosterone in the adipose tissues , developed visceral obesity and exhibited pronounced symptoms of mets . activities include screening of potential compounds from natural resources and synthesizing the inhibitor through computer modeling strategy . a selective and specific reductase inhibitor will prevent side effects and visceral obesity . on a different note , carbohydrate metabolism has been linked to glucocorticoids formation and modification of 11-hsd1 activity , whereby targeted inhibition of adipocyte glucose-6-phosphate transport and pentose pathway , reduce 11-hsd1 activity . taking this into account , it is probably necessary to simultaneously monitor energy expenditure when developing an 11-hsd1 inhibitor . the ability of antioxidants to restore and maintain normal gut physiology is receiving much attention lately . as reported by jurgonski et al . , antioxidants improve glycemia , atherogenic index , antioxidant status and gut function . the authors show that ethanol extract of the chicory seeds containing 9.6% caffeoylquinic acids normalizes the total content of short - chain fatty acids in the cecal digesta , which was decreased in animals receiving high cholesterol and fructose diet . in another study , grape , which is rich in polyphenols , stimulates the proliferation of various species of lactobacillus . outcome of the study suggests that plant foods with high dietary fiber and polyphenols content enhance git health by promoting a beneficial microbiota profile . meanwhile , antioxidant resveratrol given to hf - fed mice has helped to re - adjust the level of active glp1 in the portal vein and intestine back to basal levels . resveratrol also normalizes hf - diet - induced modification of cecal bacterial composition and decreases the elevated colonic tnf-. moreover , because melatonin increases the secretion of mucosa - protecting agents and prevents intestinal inflammation , food rich in serotonin and tryptophan may well be a non - pharmacological treatment to alleviate obesity . table 1 summarizes treatments that may potentially counteract the effect of hf - diet on gut physiology . since gut is the first line of absorption , modulating molecular pathways that are activated by luminal lipids is probably a more effective mechanism than targeting other tissues in the body . studies of the gut  brain  liver neuronal axis have shown that excessive fat impairs the signaling mechanism and hepatic glucose homeostasis . in addition , hf diet increases the release of tnf- from the gut , alters mucosal immunity , activates mast cells , increases vascular permeability , and disrupts the intestinal basement membranes . absorption of dietary fat enables uptake of lps , which further increases the secretion of pro - inflammatory cytokines and intestinal permeability . gut microbiota have received considerable interest over the last decade , seemingly due to increasing evidence of microbiota regulating fat storage , and are playing a pivotal role in governing obesity development . more important , hf diet promotes inflammation and obesity by interacting with and altering gut microbiota composition . with reference to studies of gut microbiota , antibiotics are without doubt an obvious and straightforward choice of treatment to restore the altered microbiota profile . however , as the first line of body defense against harmful pathogens , git is arguably the largest immune system in our body . these findings collectively indicate the coexistence of intestinal defense mechanisms and microbiota , working in concert in maintaining mucosal homeostasis . therefore , it is tempting to suggest that one of the reasons for obesity development is the changes in the microbiota composition superceding the protective mechanism that the gut possesses . this may be similar to gastric ulcer that occurs as a result of an imbalance between acid and bicarbonate secretion . unless the cause of obesity is confounded by genetic factors , dietary antioxidants , which may preserve gut function and restore the anatomical and physiological changes in the gut , might be an area that is worthwhile to explore further . in addition to their ability to promote the normal physiological function of the gut , dietary antioxidants are expected to be devoid of side effects that may accompany the use of antibiotics .
obesity is a metabolic disorder and fundamental cause of other fatal diseases including atherosclerosis and cancer . 
 one of the main factor that contributes to the development of obesity is high - fat ( hf ) consumption . 
 lipid ingestion will initiate from the gut feedback mechanisms to regulate glucose and lipid metabolisms . 
 but these lipid - sensing pathways are impaired in hf - induced insulin resistance , resulting in hyperglycemia . 
 besides that , duodenal lipid activates mucosal mast cells , leading to the disruption of the intestinal tight junction . 
 lipopolysaccharide that is co - transited with dietary fat postprandially , promotes the release of cytokines and the development of metabolic syndrome . 
 hf - diet also alters microbiota composition and enhances fat storage . 
 although gut is protected by immune system and contains high level of antioxidants , obesity developed presumably when this protective mechanism is compromised by the presence of excessive fat . 
 several therapeutic approaches targeting different pathways have been proposed . there may be no one single most effective treatment , but all aimed to prevent obesity . 
 this review will elaborate on the physiological and molecular changes in the gut that lead to obesity , and will provide a summary of potential treatments to manage these pathophysiological changes .