title: 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease? Obesity, Behavioral Lifestyle Factors, and Risk of Acute Coronary Events Effects of Exercise Amount and Intensity on Abdominal Obesity and Glucose Tolerance in Obese Adults Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. The joint effects of physical activity and body mass index on coronary heart disease risk in women. Assessing Causality in the Association between Child Adiposity and Physical Activity Levels: A Mendelian Randomization Analysis Reduction in Obesity and Related Comorbid Conditions after Diet-Induced Weight Loss or Exercise-Induced Weight Loss in Men Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies Associations of Cardiorespiratory Fitness and Obesity With Risks of Impaired Fasting Glucose and Type 2 Diabetes in Men Relationship of physical activity vs body mass index with type 2 diabetes in women. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. Body-mass index and mortality among 1.46 million white adults.
abstract: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading , despite our best efforts to improve the design and analysis of studies . Mendelian r and omization-the r and om assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures . The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies . Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian r and omization and are described . The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study , that polymorphisms may have several phenotypic effects associated with disease , the lack of suitable polymorphisms for study ing modifiable exposures of interest , and canalization-the buffering of the effects of genetic variation during development . Nevertheless , Mendelian r and omization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to underst and ing and preventing the adverse effects on human health of modifiable exposures Background — Whether physical activity reduces the impact of obesity on the risk of acute coronary events is much debated . However , little is known about the role of other potentially modifiable lifestyle factors in combination with obesity . Methods and Results — We followed up 54 783 women and men from the prospect i ve Danish Diet , Cancer and Health study who were 50 to 64 years at baseline ( 1993 to 1997 ) and free of coronary artery disease and cancer . During a median of 7.7 years , 1127 incident cases of acute coronary syndrome ( ACS ) occurred . After multivariable adjustments , each unit of body mass index was associated with a 5 % and 7 % higher risk of ACS among women and men , respectively ( both P<0.0001 for trend ) . Overweight ( body mass index , 25 to 29.9 kg/m2 ) and obesity ( body mass index ≥30 kg/m2 ) were associated with a higher risk of ACS among the physically active and inactive , in nonsmokers and smokers , and among those who adhered more or less to a heart-healthy dietary pattern . Obese individuals who were active 1 to 3.5 h/wk had a lower risk than sedentary , obese individuals . In addition , obese nonsmokers had a lower risk than obese smokers . Adherence to a healthy diet  was associated with a lower risk of ACS ; however , the relative risk was not different among obese individuals with the most healthy diet versus obese individuals with a less healthy diet . Conclusions — Obesity confers an elevated risk of ACS in both healthy and less healthy subgroups of lifestyle behaviors . Adherence to healthy lifestyle behaviors was associated with a lower risk even among obese individuals Editors ' Notes Context Whether there is added benefit from performing the same amount of exercise at a higher intensity is unclear . Contribution In this 24-week study , participants r and omly assigned to complete the same total amount of exercise at higher or lower intensities had similar reductions in waist circumference and weight .  High-intensity exercise alone improved 2-hour glucose tolerance and led to the greatest increase in cardiorespiratory fitness . Caution The importance of improved 2-hour glucose tolerance in participants without diabetes is unclear . Implication For the same amount of exercise , higher-intensity exercise may not result in greater reduction in waist circumference or weight but may provide benefits in glucose tolerance and cardiorespiratory fitness . The high prevalence of obesity and associated type 2 diabetes mellitus among adults presents a major public health challenge ( 1 ) . Physical inactivity is a significant determinant of obesity , and most adults in the United States are inactive ( 2 ) . Although progress has been made to eluci date the effects of exercise as a strategy for reducing obesity and related glucose tolerance , the specific exercise exposures required to achieve optimal benefit continue to be the source of considerable uncertainty and debate . Implicit within current guidelines for physical activity and health is the observation that 75 minutes of weekly high-intensity exercise is equivalent to 150 minutes of weekly lower-intensity exercise ( 3 , 4 ) . Therefore , guidelines suggest that there are no added health benefits of high-intensity exercise other than the shorter time frame needed to expend the appropriate amount of energy . Thus , the benefits of engaging in high-intensity exercise are attributed to the greater amount of energy expenditure per unit of time and do not relate to intensity per se ( 3 ) . The scientific committee report from which current guidelines were developed recognized that many unanswered issues exist in response to the question of how much of what type of activity is appropriate for a given health outcome , and acknowledged that future investigations need to evaluate the effects of exercise intensity at fixed amounts of energy expenditure . We therefore performed a r and omized clinical trial to investigate the separate effects of habitual exercise differing in amount and intensity on abdominal obesity and glucose tolerance . We studied abdominally obese adults because they are at substantially increased risk for morbidity ( 5 ) and mortality ( 6 ) and because it is estimated that 60 % of men and 45 % of women between the ages of 35 and 65 years in the United States are abdominally obese ( 7 ) . Methods Setting and Participants Details of the trial design and methods are published ( 8) . We conducted a 24-week , single-center , parallel-group , r and omized , controlled trial between 2009 to 2013 . Potential participants were excluded if they reported a history of heart disease , stroke , or any condition that would prevent them from engaging in exercise ; were already engaging in 2 or more planned exercise sessions per week ; or were diabetic . All participants provided informed consent before participation . The study was approved by the Queen 's University Health Sciences Research Ethics Board , Kingston , Ontario , Canada . Interventions Participants were r and omly assigned to 1 of the following groups : control ( no exercise ) or 5 sessions per week of low-amount , low-intensity exercise ( LALI ) ( 180 and 300 kcal/session for women and men , respectively , at 50 % of maximum oxygen consumption [ V̇o 2peak ] ) ; high-amount , low-intensity exercise ( HALI ) ( 360 and 600 kcal/session for women and men , respectively , at 50 % of V̇o 2peak ) ; or high-amount , high-intensity exercise ( HAHI ) ( 360 and 600 kcal/session for women and men , respectively , at 75 % of V̇o 2peak ) . Exercise Interventions All participants performed walk/jog exercise consistent with consensus recommendations on a treadmill for the time required to achieve the desired amount of exercise ( energy expenditure in kilocalories per session , relative to V̇o 2peak ) 5 times per week for 24 weeks . Using the heart rate and V̇o 2 data obtained from the baseline exercise test , we assigned the target heart rate associated with a V̇o 2peak of approximately 50 % ( LALI and HALI ) and approximately 75 % ( HAHI ) for each participant . At these exercise intensities , the energy expenditure targets ( exercise amount ) for women and men , respectively , were 180 and 300 kcal for the LALI group and 360 and 600 kcal for the HALI and HAHI groups . Follow-up exercise tests to measure V̇o 2peak were performed at weeks 4 , 8 , and 16 to verify the relationship between heart rate and V̇o 2 . Continual adjustment of the heart rateV̇o 2 relationship accounted for improvement in cardiorespiratory fitness ( CRF ) , which alters the time required to achieve the prescribed exercise amount ( for example , energy expenditure ) . Heart rate was monitored continuously for all exercise participants at every session to ensure adherence to the prescribed exercise intensity . All exercise sessions were supervised , and all exercise participants were asked not to engage in any structured exercise outside of the supervised sessions . Nonexercise Control Group Participants in the control group were asked to maintain their level of physical activity throughout the trial and received diet composition advice similar to that received in the exercise groups . Daily Physical Activity Unsupervised physical activity was monitored using ActiGraph GT3X accelerometers for 1-week periods at baseline and at 8 , 16 , and 25 weeks . Participants were required to wear the accelerometer for at least 4 days each period . Established accelerometer cut points were used to estimate physical activity and sedentary time ( 9 ) . Dietary Regimen During a 1-week baseline period , participants were instructed to maintain baseline body weight by monitoring their calorie intake and recording their daily consumption of self-selected foods . During the intervention , participants were instructed to maintain the calorie intake targets measured during baseline . All participants were prescribed a balanced diet and were asked to su bmi t daily dietary intake records during the intervention . Two weeks of records for all groups were analyzed using a computerized program to assess the accuracy of self-reported records . Outcomes and Follow-up Primary outcome variables were waist circumference ( WC ) , which was measured at the superior edge of the iliac crest ( 10 ) at baseline and at 8 (  exercise groups only ) , 16 , and 24 weeks , and 2-hour glucose level , which was measured in response to a 2-hour , 75-g oral glucose tolerance test between 36 and 48 hours after the last exercise session at baseline and at 16 and 24 weeks ( 8) . Secondary outcomes included CRF ( V̇o 2peak ) assessed by using st and ard open-circuit spirometry techniques with a mass flow sensor ( SensorMedics ) during a grade d exercise test in which participants walked on a treadmill at a self-selected speed at 0 elevation for 3 minutes , after which the incline was increased every 2 minutes until the participant stopped voluntarily . Levels of glucose , triglycerides , high- and low-density lipoprotein cholesterol , and insulin and blood pressure were measured using established procedures ( 8) . The Matsuda index ( an indication of insulin sensitivity ) was calculated as follows : ( 10000/[{fasting glucose levelfasting insulin level}{mean glucose levelmean insulin level during the oral glucose tolerance test}]1/2 ) ( 11 ) . There were separate assessment and intervention personnel , and all assessment personnel were blinded to participant r and omization assignment . Sample Size and Power Sample size was determined for WC and 2-hour glucose level on the basis of reduction after treatment . Previous trials suggested that exercise-induced weight loss of approximately 6 % was associated with WC reductions of 6.9 cm ( SD , 2.6 ) in men ( 12 ) and 6.5 cm ( SD , 2.6 ) in women ( 13 ) . For 2-hour glucose level , mean reductions of 0.70 mmol/L ( SD , 1.9 ) ( 12.6 mg/dL [ SD , 34.2 ] ) and 0.94 mmol/L ( SD , 0.7 ) ( 16.9 mg/dL [ SD , 12.6 ] ) were seen in men and women , respectively ( 12 , 13 ) . The sample size calculation incorporated the larger SDs for WC and 2-hour glucose level . The sample -size formula ( equation 13 of Overall and Doyle [ 14 ] ) relevant to the repeated- measures analysis of variance design was applied . The formula is based on a simple 2-group comparison of the pretreatment and posttreatment outcome changes , and it accounts for the correlation between the pretreatment and posttreatment outcome variables . With a correlation of 0.7 between pretreatment and posttreatment glucose tolerance and WC , and allowance for a dropout rate of 30 % , a sample of 40 men or women with 28 completers in each treatment group gives more than 85 % power to detect a mean difference of 2 cm in WC and a mean difference of 1.9 mmol/L ( 34.2 mg/dL ) in glucose tolerance between any 2 treatment groups . R and omization Participants were r and omly assigned to the 4 groups using the method of permuted blocks , with r and om block sizes of 4 , 8 , or 12 within strata . R and omization was stratified by sex and age , with a fifth stratum for the few couples participating to ensure that they were r and omly assigned to the same treatment . The computer-generated r and omization list was maintained by an independent statistician otherwise uninvolved in the study and was concealed from study personnel until the time of r and omization . After baseline data collection , the study coordinator contacted the statistician by e-mail to obtain treatment assignment . Statistical Analysis Analyses were done on an intention-to-treat basis ( 15 ) . All r and omly assigned participants were included in the analyses . Differences in continuous and categorical variables between dropouts and participants who completed the study were examined by using a 2-tailed t test and a chi-square test , respectively . For WC , 2-hour glucose level , CONTEXT Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for underst and ing the development of fat mass and obesity . Experimental overfeeding in humans is a unique situation to tackle these events . OBJECTIVE Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain . RESEARCH DESIGN AND METHODS Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet ( + 760 kcal/d ) for 2 months .  Subcutaneous abdominal adipose tissue biopsies were taken for histology , transcriptomics , and Western blotting in the basal state , after 14 d , and at the end of the protocol . RESULTS Overfeeding significantly increased body weight ( + 2.5 kg ) and fat mass . Reorganization of gene expression patterns occurred in adipose tissue with an up-regulation of numerous genes involved in lipid metabolism and storage , followed by clusters of genes related to angiogenesis and extracellular matrix remodeling . Histological examination showed increased microvascular density and connective tissue deposition after 56 d of overfeeding , with no changes in the number of macrophages or inflammatory cells . Inhibition of the canonical Wnt/β-catenin signaling pathway and induction of the renin-angiotensin system might be implicated in the remodeling of sc adipose tissue . CONCLUSIONS We characterize the coordinated and time-dependent processes that occur in human adipose tissue during the early phase of weight gain in healthy subjects and identify pathways representing potential targets in pathologies of adipose development , including obesity BACKGROUND Physical activity and body mass index ( calculated as weight in kilograms divided by height in meters squared ) independently alter the risk of coronary heart disease ( CHD ) ; however , their combined effect on CHD is not established . Our objective was to study the combined association of physical activity and body mass index on CHD . METHODS Prospect i ve cohort study of 38,987 women free of cardiovascular disease , cancer , and diabetes at baseline in the Women 's Health Study , with 10.9 mean years of follow-up .  Weight , height , and recreational activities were reported on entry . Body mass index was categorized as normal weight ( < 25 ) , overweight ( 25 to < 30 ) , and obese ( > or = 30 ) . Active was defined as 1000 kilocalories or more expended on recreational activities weekly . Six joint body weight-physical activity categories were defined . The main outcome measure was the occurrence of incident CHD during follow-up , defined as a cardiovascular event including nonfatal myocardial infa rct ion , coronary artery bypass graft , percutaneous transluminal coronary angioplasty , or CHD death . RESULTS A total of 948 cases of incident CHD occurred during follow-up . Higher body mass index and physical inactivity were individual predictors of CHD . In joint analyses , compared with active normal-weight individuals , the multivariate-adjusted hazard ratios ( 95 % confidence intervals ) were 1.54 ( 1.14 - 2.08 ) for overweight-active ; 1.87 ( 1.29 - 2.71 ) for obese-active ; 1.08 ( 0.84 - 1.39 ) for normal weight-inactive ; 1.88 ( 1.46 - 2.42 ) for overweight-inactive ; and 2.53 ( 1.94 - 3.30 ) for obese-inactive . Increasing levels of walking also result ed in significant reductions in CHD risk for overweight and obese individuals . CONCLUSIONS The risk of CHD associated with elevated body mass index is considerably reduced by increased physical activity levels . However , the risk is not completely eliminated , reinforcing the importance of being lean and physically active Here , Timpson and colleagues performed a Mendelian R and omization analysis to determine whether childhood adiposity causally influences levels of  physical activity .  The results suggest that increased adiposity causes a reduction in physical activity  in children ; however , this study does not exclude lower physical activity also leading to increasing adiposity . Please see later in the article for the Editors ' In 1997 , the World Health Organization published a l and mark document recognizing obesity as a worldwide disease that poses a serious threat to public health ( 1 ) . Persons who are overweight or obese have substantially increased risk for morbidity from numerous chronic disorders , such as diabetes ( 2 , 3 ) , hypertension ( 4 , 5 ) , and cardiovascular disease ( 6 , 7 ) . Obesity-related health risk is greater when excess fat is deposited in the abdomen region because this phenotype is a stronger predictor of cardiovascular disease and type 2 diabetes mellitus than general obesity is ( 8 - 11 ) . This may be partially explained by excess accumulation of visceral fat , an independent correlate of insulin resistance ( 9 - 11 ) and dyslipidemia ( 8 , 9 ) . These observations highlight the need to identify appropriate treatment strategies to prevent and reduce obesity and suggest that the effectiveness of these treatments would be enhanced if abdominal obesity , particularly visceral fat , was substantially reduced . Diet restriction remains the most common method of obesity reduction ( 12 ) . Despite the observation that low levels of physical activity are a major cause of obesity ( 13 ) , increased physical activity alone is not thought to be a useful strategy for obesity reduction . Some reports have suggested that physical activity in obese adults results in only modest weight loss ( approximately 1 to 2 kg ) independent of the effects of diet restriction ( 14 ) . However , these conclusions are drawn from studies in which individual energy intake and expenditure were not rigorously controlled or accurately measured ( 15 - 17 ) . Moreover , in most studies , the negative energy balance induced by exercise was modest enough that substantial weight loss was not expected ( 15 - 17 ) . Currently , no compelling evidence supports the observation that exercise alone is not a useful method for reducing total or abdominal obesity . It is well known that a single exercise session is associated with a significant improvement in insulin-stimulated glucose uptake ( 18 , 19 ) . It is also clear that weight loss is associated with an improvement in insulin action ( 20 - 24 ) . It is unclear , however , whether regular exercise improves glucose metabolism after the short-term effects of exercise and changes in body fat distribution are considered . Segal and colleagues ( 25 ) controlled for the confounding effect of the last exercise session and body composition changes and found that exercise had no independent effect on insulin sensitivity ( 25 ) . Given the established importance of insulin resistance as an antecedent to both cardiovascular disease and type 2 diabetes mellitus ( 26 ) , it is important to clarify whether exercise improves insulin action independent of fat loss . We performed a r and omized , controlled trial to determine the independent effect of diet-induced or exercise-induced weight loss on obesity and insulin resistance in moderately obese men . We also evaluated whether exercise without weight loss was associated with reductions in abdominal obesity and insulin resistance . Methods Participants Participants were recruited from Kingston , Ontario , Canada , a typical suburban region , through the general media . We selected men with a body mass index greater than 27 kg/m2 and a waist circumference greater than 100 cm whose weight had been stable ( 2 kg ) for 6 months before study entry . Participants were nonsmokers who consumed an average of fewer than two alcoholic beverages per day , had a sedentary lifestyle , and took no medications known to affect the principal outcome measures . All participants had a preparticipation medical examination that included screening for normal glucose tolerance and plasma lipid profile . A computer program was used to r and omly assign eligible men to one of the following four groups : control , diet-induced weight loss , exercise-induced weight loss , and exercise without weight loss ( Figure 1 ) . Of the 101 participants who were r and omly assigned to groups , 34 chose not to participate because they were dissatisfied with their assigned group , 5 were diabetic or dyslipidemic , and 3 were relocated because of job transfers . Those who chose not to participate and those who completed the trial were similar with regard to anthropometric variables . In addition , those who completed the trial were similar to those who did not in each group ( P > 0.10 ) . Baseline characteristics among groups were similar for all participants ( Table 1 ) . All participants gave fully informed written consent . The study was conducted in accordance with the ethical guidelines of Queen 's University . The participants did not receive monetary compensation . Figure 1 . Flow of participants through the study . Table 1 . Selected Anthropometric , Magnetic Resonance Imaging , and Metabolic Variables before Treatment and 3 Months after Treatment Diet and Exercise Regimen During the baseline period , daily energy requirements for all participants were determined by estimating resting energy expenditure and multiplying the obtained value by a factor of 1.5 ( 27 ) . All participants followed a weight maintenance diet ( 55 % to 60 % carbohydrate , 15 % to 20 % protein , and 20 % to 25 % fat ) for a 4- to 5-week baseline period . During this period , body weight was monitored to determine the accuracy of the prescribed energy requirement , which was adjusted accordingly to maintain body weight . Controls were asked to maintain body weight throughout the 12-week treatment period . Participants in the diet-induced weight loss group were asked to reduce the isocaloric diet by 700 kcal/d during the treatment period to achieve a weekly weight loss of approximately 0.6 kg . To lose the same amount of weight , participants in the exercise-induced weight loss group were asked to maintain the isocaloric diet for the duration of the treatment period and to perform exercise that expended 700 kcal/d . Participants assigned to exercise without weight loss were asked to maintain body weight . Therefore , they consumed enough calories to compensate for the energy expended during the daily exercise sessions ( approximately 700 kcal ) . At the end of the treatment period , isocaloric requirements were determined and prescribed for a 2-week weight stabilization period . All participants were free-living and consumed self-selected foods .  No vitamins or other nutritional supplements were prescribed . Each person participated in a series of weekly 1-hour seminars in which a dietitian taught proper food selection and preparation . Participants were told that the composition of the maintenance and energy-reduced diets should be approximately 55 % to 60 % carbohydrate , 15 % to 20 % protein , and 20 % to 25 % fat . Participants kept and analyzed daily , detailed food records for the duration of the study period ( approximately 20 weeks ) ; the study dietitian also review ed these records . For the 2-week period during which doubly labeled water measurements were acquired ( weeks 6 and 7 ) , the diet records were analyzed by using a computerized program ( Food Processor , Esha Research , Salem , Oregon ) . Participants in both exercise groups performed daily exercise ( brisk walking or light jogging ) on a motorized treadmill for the duration of the 12-week trial . The length of each exercise session was determined by the time required to expend 700 kcal . Participants were asked to exercise at an intensity not greater than 70 % of their peak oxygen uptake ( Vo 2 ) ( approximately 80 % of maximal heart rate ) . Energy expenditure was determined by using the heart rate and oxygen consumption data that were obtained from the pretreatment grade d exercise test and were adjusted according to the results of two subsequent tests performed at weeks 4 and 8 . During each session , heart rate was monitored every 5 minutes by using an automated heart rate monitor ( Polar Oy , Kempele , Finl and ) . All exercise sessions were by appointment and were supervised . Peak Vo 2 was determined by using a grade d treadmill test and st and ard open-circuit spirometry techniques ( SensorMedics , Yorba Linda , California ) . Energy Expenditure Total energy expenditure for 14 days was measured by using a two-point doubly labeled water method ( 28 ) . Deuterium enrichment was analyzed by using a 903 deuterium dual-inlet isotope ratio mass spectrometer ( VG Isogas , Cheshire , United Kingdom ) . Oxygen-18 was determined by using a SIRA 12 isotope ratio mass spectrometer ( VG Isogas ) . Total energy expenditure was calculated by using the DeWeir formula ( 29 ) . After an overnight stay in the hospital , resting metabolic rate was measured at 7:00 a.m. by using indirect calorimetry with a modified mask system ( Teem 100 , Aerosport , Inc. , Ann Arbor , Michigan ) . Values were obtained for 30 minutes , and the last 25 minutes were used to determine resting metabolic rate . Resting systolic and diastolic blood pressure were measured when the participant was supine . Magnetic Resonance Imaging and Anthropometric Measurements Whole-body data from magnetic resonance imaging ( approximately 45 equidistant images ) were obtained with a General Electric 1.5-Tesla magnet ( Milwaukee , Wisconsin ) by using an established protocol described in detail elsewhere ( 30 ) . Once acquired , the data were transferred to a st and -alone work station ( Silicon Graphics , Mountain View , California ) for analysis with specially design ed computer software ( Tomovision , Inc. , Montreal , Canada ) , the procedures for which are described elsewhere ( 31 ) . For adipose tissue ( fat ) and skeletal muscle , volume units ( L ) were converted to mass units ( kg ) by multiplying the volumes by the assumed constant density for fat ( 0.92 kg/L ) and fat-free skeletal muscle ( 1.04 kg/L ) ( 32 ) . All anthropometric circumference measurements were obtained by using st and ard procedures described elsewhere ( 30 ) . Insulin Sensitivity and Glucose Tolerance Participants consumed a weight-maintenance diet consisting of at least 200 g of carbohydrate for a minimum of 4 days and were asked to avoid strenuous physical activity for 3 days before insulin Summary Background The main associations of body-mass index ( BMI ) with overall and cause-specific mortality can best be assessed by long-term prospect i ve follow-up of large numbers of people . The Prospect i ve Studies Collaboration aim ed to investigate these associations by sharing data from many studies . Methods Collaborative analyses were undertaken of  baseline BMI versus mortality  in 57 prospect i ve studies with 894 576 participants , mostly in western Europe and North America ( 61 % [ n=541 452 ] male , mean recruitment age 46 [ SD 11 ] years , median recruitment year 1979 [ IQR 1975–85 ] , mean BMI 25 [ SD 4 ] kg/m2 ) . The analyses were adjusted for age , sex , smoking status , and study . To limit reverse causality , the first 5 years of follow-up were excluded , leaving 66 552 deaths of known cause during a mean of 8 ( SD 6 ) further years of follow-up ( mean age at death 67 [ SD 10 ] years ) : 30 416 vascular ; 2070 diabetic , renal or hepatic ; 22 592 neoplastic ; 3770 respiratory ; 7704 other . Findings In both sexes , mortality was lowest at about 22·5–25 kg/m2 . Above this range , positive associations were recorded for several specific causes and inverse associations for none , the absolute excess risks for higher BMI and smoking were roughly additive , and each 5 kg/m2 higher BMI was on average associated with about 30 % higher overall mortality ( hazard ratio per 5 kg/m2 [ HR ] 1·29 [ 95 % CI 1·27–1·32 ] ) : 40 % for vascular mortality ( HR 1·41 [ 1·37–1·45 ] ) ; 60–120 % for diabetic , renal , and hepatic mortality ( HRs 2·16 [ 1·89–2·46 ] , 1·59 [ 1·27–1·99 ] , and 1·82 [ 1·59–2·09 ] , respectively ) ; 10 % for neoplastic mortality ( HR 1·10 [ 1·06–1·15 ] ) ; and 20 % for respiratory and for all other mortality ( HRs 1·20 [ 1·07–1·34 ] and 1·20 [ 1·16–1·25 ] , respectively ) . Below the range 22·5–25 kg/m2 , BMI was associated inversely with overall mortality , mainly because of strong inverse associations with respiratory disease and lung cancer . These inverse associations were much stronger for smokers than for non-smokers , despite cigarette consumption per smoker varying little with BMI . Interpretation Although other anthropometric measures ( eg , waist circumference , waist-to-hip ratio ) could well add extra information to BMI , and BMI to them , BMI is in itself a strong predictor of overall mortality both above and below the apparent optimum of about 22·5–25 kg/m2 . The progressive excess mortality above this range is due mainly to vascular disease and is probably largely causal . At 30–35 kg/m2 , median survival is reduced by 2–4 years ; at 40–45 kg/m2 , it is reduced by 8–10 years ( which is comparable with the effects of smoking ) . The definite excess mortality below 22·5 kg/m2 is due mainly to smoking-related diseases , and is not fully explained . Funding UK Medical Research Council , British Heart Foundation , Cancer Research UK , EU BIOMED programme , US National Institute on Aging , and Clinical Trial Service Unit ( Oxford , UK ) OBJECTIVE —The purpose of this study was to examine the associations of cardiorespiratory fitness ( hereafter fitness ) and various obesity measures with risks of incident impaired fasting glucose ( IFG ) and type 2 diabetes .  RESEARCH DESIGN AND METHODS —This was a prospect i ve cohort study of 14,006 men ( 7,795 for the analyses of IFG ) , who did not have an abnormal electrocardiogram or a history of heart attack , stroke , cancer , or diabetes . RESULTS —Of the men , 3,612 ( 39,610 person-years ) and 477 ( 101,419 person-years ) developed IFG and type 2 diabetes  , respectively . Compared with the least fit 20 % in multivariate analyses , IFG and type 2 diabetes risks in the most fit 20 % were 14 and 52 % lower , respectively ( both P < 0.001 ) . Men with BMI ≥30.0 kg/m2 , waist girth > 102.0 cm , or percent body fat ≥25 had 2.7- , 1.9- , and 1.3-fold higher risks for type 2 diabetes , respectively , compared with those for nonobese men ( all P < 0.01 ) , and the results for IFG were similar . In the combined analyses , obese unfit ( least fit 20 % ) men had a 5.7-fold higher risk for type 2 diabetes compared with normal-weight fit ( most fit 80 % ) men . We observed similar trends for the joint associations of BMI and fitness with IFG and those of waist girth or percent body fat and fitness with both IFG and type 2 diabetes . CONCLUSIONS —Low fitness and obesity increased the risks of IFG and type 2 diabetes by approximately similar magnitudes . When considered simultaneously , fitness attenuated but did not eliminate the increased risks of IFG and type 2 diabetes associated with obesity , and the highest risk was found in obese and unfit men CONTEXT Physical inactivity and body mass index ( BMI ) are established independent risk factors in the development of type 2 diabetes ; however , their comparative importance and joint relationship with diabetes are unclear . OBJECTIVE To examine the relative contributions and joint association of physical activity and BMI with diabetes . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve cohort study of 37 878 women free of cardiovascular disease , cancer , and diabetes with 6.9 years of mean follow-up .  Weight , height , and recreational activities were reported at study entry . Normal weight was defined as a BMI of less than 25 ; overweight , 25 to less than 30 ; and obese , 30 or higher . Active was defined as expending more than 1000 kcal on recreational activities per week . MAIN OUTCOME MEASURE Incident type 2 diabetes , defined as a new self-reported diagnosis of diabetes . RESULTS During the follow-up , 1361 cases of incident diabetes occurred . Individually , BMI and physical activity were significant predictors of incident diabetes . Compared with normal-weight individuals , the multivariate-adjusted hazard ratio ( HR ) was 3.22 ( 95 % confidence interval [ CI ] , 2.69 - 3.87 ) for overweight individuals and 9.09 ( 95 % CI , 7.62 - 10.8 ) for obese individuals . For overall activity ( kilocalories expended per week ) , compared with the least active first quartile , the multivariate-adjusted HRs were 0.91 ( 95 % CI , 0.79 - 1.06 ) for the second quartile , 0.86 ( 95 % CI , 0.74 - 1.01 ) for the third , and 0.82 ( 95 % CI , 0.70 - 0.97 ) for the fourth ( P for trend = .01 ) . In the combined analyses , overweight and obese participants , whether active or inactive , had significantly elevated risks , compared with normal-weight active individuals . The multivariate-adjusted HRs were 1.15 ( 95 % CI , 0.83 - 1.59 ) for normal-weight inactive , 3.68 ( 95 % CI , 2.63 - 5.15 ) for overweight active , 4.16 ( 95 % CI , 3.05 - 5.66 ) for overweight inactive , 11.5 ( 95 % CI , 8.34 - 15.9 ) for obese active , and 11.8 ( 95 % CI , 8.75 - 16.0 ) for obese inactive participants . CONCLUSIONS Although BMI and physical inactivity are independent predictors of incident diabetes , the magnitude of the association with BMI was greater than with physical activity in combined analyses . These findings underscore the critical importance of adiposity as a determinant of diabetes CONTEXT Low levels of cardiorespiratory fitness are associated with high risk of mortality , and improvements in fitness are associated with reduced mortality risk . However , a poor underst and ing of the physical activity-fitness dose response relation remains . OBJECTIVE To examine the effect of 50 % , 100 % , and 150 % of the NIH Consensus Development Panel recommended physical activity dose on fitness in women . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial of 464 sedentary , postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg . Enrollment took place between April 2001 and June 2005 in the Dallas , Tex , area . INTERVENTION Participants were r and omly assigned to 1 of 4 groups : 102 to the nonexercise control group and 155 to the 4-kcal/kg , 104 to the 8-kcal/kg , and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period . Target training intensity was the heart rate associated with 50 % of each woman 's peak Vo2 . MAIN OUTCOME MEASURE The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption ( Vo2abs , L/min ) . RESULTS The mean ( SD ) baseline Vo2abs values were 1.30 ( 0.25 ) L/min . The mean ( SD ) minutes of exercising per week were 72.2 ( 12.3 ) for the 4-kcal/kg , 135.8 ( 19.5 ) for the 8-kcal/kg , and 191.7 ( 33.7 ) for the 12-kcal/kg per week exercise groups . After adjustment for age , race/ethnicity , weight , and peak heart rate , the exercise groups increased their Vo2abs compared with the control group by 4.2 % in the 4-kcal/kg , 6.0 % in the 8-kcal/kg , and 8.2 % in the 12-kcal/kg per week groups ( P<.001 for each vs control ; P for trend < .001 ) . There was no treatment x subgroup interaction for age , body mass index , weight , baseline Vo2abs , race/ethnicity , or baseline hormone therapy use . There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group . CONCLUSION In this study , previously sedentary , overweight or obese postmenopausal women experienced a grade d dose-response change in fitness across levels of exercise training . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00011193 BACKGROUND A high body-mass index ( BMI , the weight in kilograms divided by the square of the height in meters ) is associated with increased mortality from cardiovascular disease and certain cancers , but the precise relationship between BMI and all-cause mortality remains uncertain . METHODS We used Cox regression to estimate hazard ratios and 95 % confidence intervals for an association between BMI and all-cause mortality , adjusting for age , study , physical activity , alcohol consumption , education , and marital status in pooled data from 19 prospect i ve studies encompassing 1.46 million white adults , 19 to 84 years of age ( median , 58 ) . RESULTS The median baseline BMI was 26.2 . During a median follow-up period of 10 years ( range , 5 to 28 ) , 160,087  deaths were identified . Among healthy participants who never smoked , there was a J-shaped relationship between BMI and all-cause mortality . With a BMI of 22.5 to 24.9 as the reference category , hazard ratios among women were 1.47 ( 95 percent confidence interval [ CI ] , 1.33 to 1.62 ) for a BMI of 15.0 to 18.4 ; 1.14 ( 95 % CI , 1.07 to 1.22 ) for a BMI of 18.5 to 19.9 ; 1.00 ( 95 % CI , 0.96 to 1.04 ) for a BMI of 20.0 to 22.4 ; 1.13 ( 95 % CI , 1.09 to 1.17 ) for a BMI of 25.0 to 29.9 ; 1.44 ( 95 % CI , 1.38 to 1.50 ) for a BMI of 30.0 to 34.9 ; 1.88 ( 95 % CI , 1.77 to 2.00 ) for a BMI of 35.0 to 39.9 ; and 2.51 ( 95 % CI , 2.30 to 2.73 ) for a BMI of 40.0 to 49.9 . In general , the hazard ratios for the men were similar . Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up . CONCLUSIONS In white adults , overweight and obesity ( and possibly underweight ) are associated with increased all-cause mortality . All-cause mortality is generally lowest with a BMI of 20.0 to 24.9
target: We argue that despite inconsistencies in the definition , patterns across studies clearly show that healthy obesity is a state of intermediate disease risk .
  Expert commentary : Given the current state of population -level evidence , we conclude that obesity and metabolic dysfunction are inseparable and that healthy obesity is best viewed only as a state of relative health but not of absolute health .
background: INTRODUCTION Obesity is a top public health priority but interventions to reverse the condition have had limited success .
  About one-in-three obese adults are free of metabolic risk factor clustering and are considered ' healthy ' , and much attention has focused on the implication s of this state for obesity management .