Lower thigh subcutaneous and higher visceral abdominal adipose tissue content both contribute to insulin resistance

It is well known that visceral adipose tissue (VAT) is associated with insulin resistance (IR). Considerable debate remains concerning the potential positive effect of thigh subcutaneous adipose tissue (TSAT). Our objective was to observe whether VAT and TSAT are opposite, synergistic or additive for both peripheral and hepatic IR. Fifty-two volunteers (21 male/31 female) between 30 and 75 years old were recruited from the general population. All subjects were sedentary overweight or obese (mean BMI 33.0 ± 3.4 kg/m(2)). Insulin sensitivity was determined by a 4-h hyperinsulinemic-euglycemic clamp with stable isotope tracer dilution. Total body fat and lean body mass were determined by dual X-ray absorptiometry. Abdominal and mid-thigh adiposity was determined by computed tomography. VAT was negatively associated with peripheral insulin sensitivity, while TSAT, in contrast, was positively associated with peripheral insulin sensitivity. Subjects with a combination of low VAT and high TSAT had the highest insulin sensitivity, subjects with a combination of high VAT and low TSAT were the most insulin resistant. These associations remained significant after adjusting for age and gender. These data confirm that visceral excess abdominal adiposity is associated with IR across a range of middle-age to older men and women, and further suggest that higher thigh subcutaneous fat is favorably associated with better insulin sensitivity. This strongly suggests that these two distinct fat distribution phenotypes should both be considered in IR as important determinants of cardiometabolic risk.     

Sex Differences in the Association of Thigh Fat and Metabolic Risk in Older Adults

We have previously shown a favorable association of subcutaneous leg fat with markers of insulin resistance and dyslipidemia in postmenopausal women. It is not known whether there is a sex dimorphism in the association of lower‐body adiposity with reduced metabolic risk. Thus, our primary aim was to determine whether the favorable association of thigh subcutaneous fat, independent of abdominal fat, is also observed in older men. Mid‐thigh and abdominal fat areas were measured by computed tomography (CT) in 108 older men and postmenopausal women (mean ± s.d.; 69 ± 7 years). Additionally, trunk and leg fat mass (FM) were measured by dual‐energy X‐ray absorptiometry (DXA). Markers of insulin resistance and dyslipidemia were determined from oral glucose tolerance tests and lipid and lipoprotein measurements, respectively. Outcomes were fasted and postchallenge (area under the curve, AUC) insulin (INS_AUC) and glucose (GLU_AUC), product of the insulin and glucose AUC (INS_AUC × GLU_AUC), triglycerides (TG), and high‐density lipoprotein (HDL)‐cholesterol. Consistent with our previous findings in postmenopausal women, adjusting for DXA trunk FM revealed a favorable association of DXA leg FM with the metabolic risk outcomes in both older men and postmenopausal women. Likewise, adjusting for CT abdominal visceral fat generally revealed a favorable association of CT thigh fat with metabolic risk outcomes in women, but not men. The discordance between the DXA and CT results in men is unclear but may be due to sex differences in visceral fat accrual. The mechanisms underlying the protective effect of thigh fat on metabolic risk factors need to be elucidated.     

Contribution of the lean body mass to insulin resistance in postmenopausal women with visceral obesity: a Monet study

Some insulin-resistant obese postmenopausal (PM) women are characterized by an android body fat distribution type and higher levels of lean body mass (LBM) compared to insulin-sensitive obese PM women. This study investigates the independent contribution of LBM to the detrimental effect of visceral fat (VF) levels on the metabolic profile. One hundred and three PM women (age: 58.0+/-4.9 years) were studied and categorized in four groups on the basis of their VF (higher vs. lower) and lean BMI (LBMI=LBM (kg)/height (m2); higher vs. lower). Measures included: fasting lipids, glucose homeostasis (by euglycemic/hyperinsulinemic clamp technique and 2-h oral glucose tolerance test (OGTT)), C-reactive protein (CRP) levels, fat distribution (by computed tomography (CT) scan), and body composition (by dual-energy X-ray absorptiometry). Women in the higher VF/higher LBMI group had lower glucose disposal and higher plasma insulin levels compared to the other groups. They also had higher plasma CRP levels than the women in the lower VF/lower LBMI group. VF was independently associated with insulin levels, measures of glucose disposal, and CRP levels (P<0.05). LBMI was also independently associated with insulin levels, glucose disposal, and CRP levels (P<0.05). Finally, significant interactions were observed between LBMI and VF levels for insulin levels during the OGTT and measures of glucose disposal (P<0.05). In conclusion, VF and LBMI are both independently associated with alterations in glucose homeostasis and CRP levels. The contribution of VF to insulin resistance seems to be exacerbated by increased LBM in PM women.     

Toll-like receptor 3 ablation prevented high-fat diet-induced obesity and metabolic disorder

Inflammation in insulin-sensitive tissues (e.g., liver, visceral adipose tissue [VAT]) plays a major role in obesity and insulin resistance. Recruitment of innate immune cells drives the dysregulation of glucose and lipid metabolism. We aimed to seek the role of Toll like receptor 3 (TLR3), a pattern recognition receptor involved in innate immunity, obesity and the metabolic disorder. TLR3 expression in liver and VAT from diet induced obese mice and in VAT from overweight women was examined. Body weight, glucose homeostasis and insulin sensitivity were evaluated in TLR3 wild-type and knockout (KO) mice on a chow diet (CD) or high-fat diet for 15 weeks. At euthanasia, blood was collected, and plasma biochemical parameters and adipokines were determined with commercial kits. Flow cytometry was used to measure macrophage infiltration and activation in VAT. Standard western blot, immunohistochemistry and quantative PCR were used to assess molecules in pathways about lipid and glucose metabolism, insulin and inflammation in tissues of liver and VAT. Utilizing human and animal samples, we found that expression of TLR3 was upregulated in the liver and VAT in obese mice as well as VAT in overweight women. TLR3-deficiency protected against high-fat diet induced obesity, glucose intolerance, insulin resistance and lipid accumulation. Lipolysis was enhanced in VAT and hepatic lipogenesis was inhibited in TLR3 KO animals. Macrophages infiltration into adipose tissue was attenuated in TLR3 KO mice, accompanied with inhibition of NF-κB-dependent AMPK/Akt signaling pathway. These findings demonstrated that TLR3 ablation prevented obesity and metabolic disorders, thereby providing new mechanistic links between inflammation and obesity and associated metabolic abnormalities in lipid/glucose metabolism.     

Soy isoflavones (Glycine max) ameliorate hypertriglyceridemia and hepatic steatosis in high fat-fed ovariectomized Wistar rats (an experimental model of postmenopausal obesity)

Obesity emerged as the major risk factor for metabolic syndrome. Postmenopausal women are more prone to develop obesity than premenopausal women. The absence of safe and effective conventional treatments for postmenopausal obesity has changed the focus to natural products as alternative remedy. We investigated the molecular basis of the effect of soy isoflavones (SIFs) on hypertriglyceridemia and hepatic steatosis in an animal model of postmenopausal obesity. Ovariectomized (OVX) and sham-operated Wistar rats were fed with high-fat diet (HFD) and normal diet for 8 weeks with and without SIF extract (150 mg/kg body weight/day). Both OVX and HFD per se and when combined caused hypertriglyceridemia, hypercholesterolemia and atherogenic lipid profile. Proteomic studies revealed that both OVX and HFD caused overexpression of hepatic lipogenic proteins, such as LXR, SREBP1, PPARγ, ACC and FAS, in association with reduced expression of lipolytic proteins, such as FXR, PPARα, insig2 and SHP. Histological analysis showed fat accumulation and morphological abnormalities in the liver of OVX and HFD rats. All these metabolic derangements were further augmented when OVX was followed by HFD. In conclusion, these findings suggest that there was a synergism in the development of deranged lipid metabolism with the coexistence of postmenopausal state and the intake of fat-rich diet. SIF extract markedly alleviated the derangement of lipid metabolism suggesting the use of this natural phytoestrogen as a strategy for relieving dyslipidemia and hepatic steatosis associated with the postmenopausal women.     

Effect of sarcopenia on cardiovascular disease risk factors in obese postmenopausal women

Objective: To compare sarcopenic‐obese and obese postmenopausal women for risk factors predisposing to cardiovascular disease (CVD) and determine whether there may be a relationship between muscle mass and metabolic risk in obese postmenopausal women. Research Methods and Procedures: In this cross‐sectional study, 22 healthy obese postmenopausal women (mean age, 66 ± 5 years; mean BMI, 27 ± 3 kg/m²) were divided into two groups matched for age (±2 years) and fat mass (FM) (±2%). Sarcopenia was defined as a muscle mass index of <14.30 kg fat‐free mass (FFM)/m² (which corresponds to 1 standard deviation below the values of a young reference population), and obesity was defined as an FM of >35% (which corresponds to the World Health Organization guidelines). FM, FFM (measured by DXA), daily energy expenditure (accelerometry), dietary intake (3‐day dietary record), and blood biochemical analyses (lipid profile, insulin, glucose, and C‐reactive protein) were obtained. Visceral fat mass (VFM) was calculated by the equation of Bertin, which estimates VFM from DXA measurements. Results: Obese women had more FFM (p = 0.006), abdominal FM (p = 0.047), and VFM (p = 0.041) and a worse lipid profile [p = 0.040 for triglycerides; p = 0.004 for high‐density lipoprotein (HDL); p = 0.026 for total cholesterol/HDL] than sarcopenic‐obese postmenopausal women. Obese women also ingested significantly more animal (p = 0.001) and less vegetal proteins (p = 0.013), although both groups had a similar total protein intake (p = 0.967). Discussion: Sarcopenia seems to be associated with lower risk factors predisposing to CVD in obese postmenopausal women. With the increase in the number of aging people, the health implications of being sarcopenic‐obese merit more attention.     

Comparison of Regional Fat Distribution and Health Risk Factors in Middle‐Aged White and African American Women: The Healthy Transitions Study

Objective: Both ethnicity and menopause appear to influence intra‐abdominal fat distribution. This study evaluated intra‐abdominal fat distribution and obesity‐related health risks in perimenopausal white and African American women. Research Methods and Procedures: Baseline data from a longitudinal study of changes in body composition and energy balance during menopause are reported. Healthy women (55 African Americans and 103 whites) who were on no medication and had at least five menstrual cycles in the previous 6 months were recruited. Body composition was assessed by DXA, and visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were assessed by computed tomography scan. SAT was divided into deep and superficial layers demarcated by the fascia superficialis. Results: African American women were slightly younger (46.7 ± 0.2 vs. 47.7 ± 0.2 years, p = 0.002) and fatter (42.4% ± 1.0% vs. 39.4% ± 0.8% body fat, p = 0.02) than white women. In unadjusted data, African Americans had significantly more total abdominal fat and total, deep, and superficial SAT than whites. After adjustment for percent body fat and age, only total and superficial SAT remained significantly higher in African Americans. VAT although slightly less in African American women, did not differ significantly by race. In multiple regression analysis, VAT was the strongest predictor of serum lipids, glucose, and insulin in women of both races, although superficial SAT was significantly associated with fasting glucose in whites. Conclusions: Middle‐aged African American women have larger SAT depots, adjusted for total body fatness, but do not differ from white women with regard to VAT. The complexity of the relationship between abdominal fat and metabolic risk is increased by ethnic differences in such associations.     

Android fat depot is more closely associated with metabolic syndrome than abdominal visceral fat in elderly people

Background

Fat accumulation in android compartments may confer increased metabolic risk. The incremental utility of measuring regional fat deposition in association with metabolic syndrome (MS) has not been well described particularly in an elderly population.

Methods and Findings

As part of the Korean Longitudinal Study on Health and Aging, which is a community-based cohort study of people aged more than 65 years, subjects (287 male, 75.9±8.6 years and 278 female, 76.0±8.8 years) with regional body composition data using Dual energy X-ray absorptiometry for android/gynoid area, computed tomography for visceral/subcutaneous adipose tissue (VAT/SAT), and cardiometabolic markers including adiponectin and high-sensitivity CRP were enrolled. We investigated the relationship between regional body composition and MS in multivariate regression models. Mean VAT and SAT area was 131.4±65.5 cm² and 126.9±55.2 cm² in men (P = 0.045) and 120.0±46.7 cm² and 211.8±65.9 cm² in women (P<0.01). Mean android and gynoid fat amount was 1.8±0.8 kg and 2.5±0.8 kg in men and 2.0±0.6 kg and 3.3±0.8 kg in women, respectively (both P<0.01). VAT area and android fat amount was strongly correlated with most metabolic risk factors compared to SAT or gynoid fat. Furthermore, android fat amount was significantly associated with clustering of MS components after adjustment for multiple parameters including age, gender, adiponectin, hsCRP, a surrogate marker of insulin resistance, whole body fat mass and VAT area.

Conclusions

Our findings are consistent with the hypothesized role of android fat as a pathogenic fat depot in the MS. Measurement of android fat may provide a more complete understanding of metabolic risk associated with variations in fat distribution.     

Effects of Exercise on Metabolic Risk Variables in Overweight Postmenopausal Women: A Randomized Clinical Trial

Objective: This study examined the effects of exercise on metabolic risk variables insulin, leptin, glucose, and triglycerides in overweight/obese postmenopausal women. Research Methods and Procedures: Sedentary women (n = 173) who were overweight or obese (BMI ≥ 25 kg/m² or ≥24 kg/m² with ≥33% body fat), 50 to 75 years of age, were randomized to 12 months of exercise (≥45 minutes of moderate‐intensity aerobic activity 5 d/wk) or to a stretching control group. Body composition (DXA) and visceral adiposity (computed tomography) were measured at baseline and 12 months. Insulin, glucose, triglycerides, and leptin were measured at baseline and 3 and 12 months. Insulin resistance was evaluated by the homeostasis model assessment formula. Differences from baseline to follow‐up were calculated and compared across groups. Results: Exercisers had a 4% decrease and controls had a 12% increase in insulin concentrations from baseline to 12 months (p = 0.0002). Over the same 12‐month period, leptin concentrations decreased by 7% among exercisers compared with remaining constant among controls (p = 0.03). Homeostasis model assessment scores decreased by 2% among exercisers and increased 14% among controls from baseline to 12 months (p = 0.0005). The exercise effect on insulin was modified by changes in total fat mass (trend, p = 0.03), such that the exercise intervention abolished increases in insulin concentrations associated with gains in total fat mass. Discussion: Regular moderate‐intensity exercise can be used to improve metabolic risk variables such as insulin and leptin in overweight/obese postmenopausal women. These results are promising for health care providers providing advice to postmenopausal women for lifestyle changes to reduce risk of insulin resistance, coronary heart disease, and diabetes.     

The Human Visceral Fat Depot Has a Unique Inflammatory Profile

Obesity can be considered as a low‐grade inflammatory condition, strongly linked to adverse metabolic outcomes. Obesity‐associated adipose tissue inflammation is characterized by infiltration of macrophages and increased cytokine and chemokine production. The distribution of adipose tissue impacts the outcomes of obesity, with the accumulation of fat in visceral adipose tissue (VAT) and deep subcutaneous adipose tissue (SAT), but not superficial SAT, being linked to insulin resistance. We hypothesized that the inflammatory gene expression in deep SAT and VAT is higher than in superficial SAT. A total of 17 apparently healthy women (BMI: 29.3±5.5 kg/m²) were included in the study. Body fat (dual‐energy X‐ray absorptiometry) and distribution (computed tomography) were measured, and insulin sensitivity, blood lipids, and blood pressure were determined. Inflammation‐related differences in gene expression (real‐time PCR) from VAT, superficial and deep SAT biopsies were analyzed using univariate and multivariate data analyses. Using multivariate discrimination analysis, VAT appeared as a distinct depot in adipose tissue inflammation, while the SAT depots had a similar pattern, with respect to gene expression. A significantly elevated (P < 0.01) expression of the CC chemokine receptor 2 (CCR2) and macrophage migration inhibitory factor (MIF) in VAT contributed strongly to the discrimination. In conclusion, the human adipose tissue depots have unique inflammatory patterns, with CCR2 and MIF distinguishing between VAT and the SAT depots.     

Elevation in cardiovascular disease risk in South Asians is mediated by differences in visceral adipose tissue

South Asians have a higher risk for cardiovascular disease (CVD) that remains largely unexplained. We hypothesized that the increased CVD risk in South Asians compared to Europeans is mediated through higher levels of visceral adipose tissue (VAT) in South Asians compared to total body fat and subcutaneous abdominal adipose tissue (SAT). South Asians (207) and Europeans (201) underwent assessment for demographics, body fat, and risk factors. Linear regression models were created by sex for each risk factor to explore mediation effects of total body fat, SAT, and VAT adjusted for age, income, smoking, and BMI (menopausal status for women). Mediation was based on changes in the ethnicity β coefficient due to additional adjustment for our adipose variable of interest and the Sobel test for mediation. South Asians had worse lipid, glucose, insulin, and C-reactive protein (CRP) levels than Europeans after adjusting for confounders. Most of these differences remained even after further adjustment by either total body fat or SAT. In contrast, VAT attenuated the ethnic differences in risk factors by 16%-52%. After adjusting for VAT, there were no longer ethnic differences in total cholesterol (TC), LDL-C, TC/HDL-C, glucose, and diastolic blood pressure (BP) in men, and in HDL-C, triglycerides (TG), TC/HDL-C, and homeostasis model (HOMA) in women, and VAT was a significant mediator for these risk factors. Higher levels of risk factors for CVD in South Asians are predominantly because of the unique phenotype of South Asians having greater VAT than Europeans even at the same BMI.     

Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults

Objective : Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population‐based cohort of obese adults. Design and Methods : Among obese participants in the Dallas Heart Study, we examined the cross‐sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. Results : In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA‐IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p < 0.001 for each). VAT independently associated with C‐reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA‐IR were significant in univariable analyses but attenuated after multivariable adjustment. Conclusion : VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub‐phenotypes with heterogeneous metabolic and atherosclerosis risk.     

Is a small muscle mass index really detrimental for insulin sensitivity in postmenopausal women of various body composition status?

Objectives: We sought to determine if a small muscle mass index (MMI) is actually detrimental for insulin sensitivity when studying a large group of postmenopausal women displaying various body composition statuses and when age and visceral fat mass (VFM) are taken into account. Methods: A cross-sectional study was conducted in 99 healthy postmenopausal women with a BMI of 28?4 kg/m(2). Fat mass and total fat-free mass (FFM) were obtained from DXA and VFM and MMI were estimated respectively by the equation of Bertin and by: Total FFM (kg)/height (m)(2). Fasting plasma insulin and glucose were obtained to calculate QUICKI and HOMA as an insulin sensitivity index. Results: Total MMI and VFM were both significantly inversely correlated with QUICKI and positively with HOMA even when adjusted for VFM. A stepwise linear regression confirmed Total MMI and VFM as independent predictors of HOMA and plasma insulin level. Conclusions: A small muscle mass might not be detrimental for the maintenance of insulin sensitivity and could even be beneficial in sedentary postmenopausal women. The impact of muscle mass loss on insulin sensitivity in older adults needs to be further investigated.     

Depot-specific regulation of glucose uptake and insulin sensitivity in HIV-lipodystrophy

Altered fat distribution is associated with insulin resistance in HIV, but little is known about regional glucose metabolism in fat and muscle depots in this patient population. The aim of the present study was to quantify regional fat, muscle, and whole body glucose disposal in HIV-infected men with lipoatrophy. Whole body glucose disposal was determined by hyperinsulinemic clamp technique (80 mU x m(-2) x min(-1)) in 6 HIV-infected men and 5 age/weight-matched healthy volunteers. Regional glucose uptake in muscle and subcutaneous (SAT) and visceral adipose tissue (VAT) was quantified in fasting and insulin-stimulated states using 2-deoxy-[18F]fluoro-D-glucose positron emission tomography. HIV-infected subjects with lipoatrophy had significantly increased glucose uptake into SAT (3.8 +/- 0.4 vs. 2.3 +/- 0.5 micromol x kg tissue(-1) x min(-1), P < 0.05) in the fasted state. Glucose uptake into VAT did not differ between groups. VAT area was inversely related with whole body glucose disposal, insulin sensitivity, and muscle glucose uptake during insulin stimulation. VAT area was highly predictive of whole body glucose disposal (r2 = 0.94, P < 0.0001). This may be mediated by adiponectin, which was significantly associated with VAT area (r = -0.75, P = 0.008), and whole body glucose disposal (r = 0.80, P = 0.003). This is the first study to directly demonstrate increased glucose uptake in subcutaneous fat of lipoatrophic patients, which may partially compensate for loss of SAT. Furthermore, we demonstrate a clear relationship between VAT and glucose metabolism in multiple fat and muscle depots, suggesting the critical importance of this depot in the regulation of glucose and highlighting the significant potential role of adiponectin in this process.     

Contributions of total and regional fat mass to risk for cardiovascular disease in older women

The aim of this study was to determine whether trunk fat mass, measured by dual-energy X-ray absorptiometry (DEXA), is predictive of insulin resistance and dyslipidemia, independently of arm and leg fat mass, in postmenopausal women. Total and regional body composition was measured by DEXA in 166 healthy, postmenopausal women (66 +/- 4 yr). Four primary markers of insulin resistance and dyslipidemia were assessed: 1) area under the curve for the insulin (INS(AUC)) response to an oral glucose tolerance test (OGTT), 2) product of the OGTT glucose and insulin areas (INS(AUC)xGLU(AUC)), 3) serum triglycerides (TG), and 4) high-density lipoprotein (HDL)-cholesterol. Trunk fat mass was the strongest independent predictor of each of the primary dependent variables. In multivariate regression models, trunk fat mass was associated with unfavorable levels of INS(AUC), INS(AUC)xGLU(AUC), TG, and HDL-C, whereas leg fat mass was favorably associated with each of these variables. Thus trunk fat is a strong independent predictor of insulin resistance and dyslipidemia in postmenopausal women, whereas leg fat appears to confer protective effects against metabolic dysfunction.     

Visceral fat, waist circumference, and BMI: impact of race/ethnicity

Objective: BMI and waist circumference are used to define risk from excess body fat. Limited data in women suggest that there may be racial/ethnic differences in visceral adipose tissue (VAT) at a given BMI or waist circumference. This study tested the hypothesis that racial/ethnic differences exist in both men and women in the relationship of anthropometric measures of body composition and computed tomography (CT)‐determined VAT or subcutaneous adipose tissue (SAT). Methods and Procedures: Subjects included 66 African American, 72 Hispanic, and 47 white men and women, aged ≥ 45. Waist circumference and BMI were measured using standard methods. Total abdominal and L4L5 VAT and SAT were measured using CT. Results: Among both men and women, groups did not differ in waist circumference or BMI. White men had greater L4L5 VAT than African‐American men, and both white and Hispanic men had greater total VAT than African‐American men. Among women, Hispanics and whites had greater L4L5 VAT than African Americans, and Hispanics had greater total VAT than African Americans. The slope of the linear relationship between BMI or waist circumference and VAT was lower in African Americans than in Hispanics and/or whites. Discussion: Middle‐aged and older African‐American men and women had lower VAT despite similar BMI and waist circumference measurements. Altered relationships between anthropometric measures and VAT may have implications for defining metabolic risk in different populations. Different waist circumference or BMI cutoff points may be necessary to adequately reflect risk in different racial/ethnic groups.     

Adiponectin is inversely associated with intramyocellular and intrahepatic lipids in obese premenopausal women

Adiponectin, an adipokine secreted by adipocytes, exerts beneficial effects on glucose and lipid metabolism and has been found to improve insulin resistance by decreasing triglyceride content in muscle and liver in obese mice. Adiponectin is found in several isoforms and the high-molecular weight (HMW) form has been linked most strongly to the insulin-sensitizing effects. Fat content in skeletal muscle (intramyocellular lipids, IMCL) and liver (intrahepatic lipids, IHL) can be quantified noninvasively using proton magnetic resonance spectroscopy ((1)H-MRS). The purpose of our study was to assess the relationship between HMW adiponectin and measures of glucose homeostasis, IMCL and IHL, and to determine predictors of adiponectin levels. We studied 66 premenopausal women (mean BMI 31.0 ± 6.6 kg/m(2)) who underwent (1)H-MRS of calf muscles and liver for IMCL and IHL, computed tomography (CT) of the abdomen for abdominal fat depots, dual-energy X-ray absorptiometry (DXA) for fat and lean mass assessments, HMW and total adiponectin, fasting lipid profile and an oral glucose tolerance test (homeostasis model assessment of insulin resistance (HOMA(IR)), glucose and insulin area under the curve). There were strong inverse associations between HMW adiponectin and measures of insulin resistance, IMCL and IHL, independent of visceral adipose tissue (VAT) and total body fat. IHL was the strongest predictor of adiponectin and adiponectin was a predictor of HOMA(IR). Our study showed that in premenopausal obese women HMW adiponectin is inversely associated with IMCL and IHL content. This suggests that adiponectin exerts positive effects on insulin sensitivity in obesity by decreasing intracellular triglyceride content in skeletal muscle and liver; it is also possible that our results reflect effects of insulin on adiponectin.     

Associations of visceral and liver fat with the metabolic syndrome across the spectrum of obesity: the AGES-Reykjavik study

Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI <25, 25-29.9, and ≥30 kg/m2, respectively). This analysis included 2,495 participants from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study with computed tomography measurements for VAT and LF. MetS was defined by ≥3 of the following: larger abdominal circumference, hypertension, elevated triglyceride (TG), low high-density lipoprotein (HDL), impaired fasting glucose (IFG), and microalbuminuria. We estimated the odds of MetS per 1-s.d. increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (odds ratios (OR) = 2.78, 1.63, and 1.43, respectively; all P < 0.01) that diminished in magnitude with increasing BMI (VAT × BMI class interaction P < 0.001). In men, VAT was related to MetS only among the overweight (OR = 1.69, P < 0.01). LF was associated with MetS in the overweight and obese groups in women (OR = 1.38 and 1.45; both P < 0.001) and in men (OR = 1.38, P = 0.01; and OR = 1.27, P = 0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals.     

Impacts of Visceral Adipose Tissue and Subcutaneous Adipose Tissue on Metabolic Risk Factors in Middle‐aged Japanese

Regional fat distribution rather than overall fat volume has been considered to be important to understanding the link between obesity and metabolic disorders. We aimed to evaluate the independent associations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with metabolic risk factors in apparently healthy middle‐aged Japanese. Participants were 1,119 men and 854 women aged 38–60 years who were not taking medications for diabetes, hypertension, or dyslipidemia. VAT and SAT were measured by use of computed tomography (CT) scanning. VAT and SAT were significantly and positively correlated with each other in men (r = 0.531, P < 0.001) and women (r = 0.589, P < 0.001). In multiple regression analyses, either measure of abdominal adiposity (VAT or SAT) was positively associated with blood pressure, fasting plasma glucose, and log triglyceride (P < 0.001) and inversely with high‐density lipoprotein (HDL)‐cholesterol (P < 0.001). When VAT and SAT were simultaneously included in the model, the association of VAT with triglycerides was maintained (P < 0.001) but that of SAT was lost. The same was true for HDL‐cholesterol in women. For fasting plasma glucose, the association with VAT was strong (P < 0.001) and the borderline association with SAT was maintained (P = 0.060 in men and P = 0.020 in women). Both VAT and SAT were independently associated with blood pressure (P < 0.001). Further adjustment for anthropometric indices resulted in the independent association only with VAT for all risk factors. In conclusion, impacts of VAT and SAT differed among risk factors. VAT showed dominant impacts on triglyceride concentrations in both genders and on HDL‐cholesterol in women, while SAT also had an independent association with blood pressure.     

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.