Faidon Magkos

Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity

Visceral adipose tissue (VAT) is an important risk factor for obesity-related metabolic disorders. Therefore, a reduction in VAT has become a key goal in obesity management. However, VAT is correlated with intrahepatic triglyceride (IHTG) content, so it is possible that IHTG, not VAT, is a better marker of metabolic disease. We determined the independent association of IHTG and VAT to metabolic function, by evaluating groups of obese subjects, who differed in IHTG content (high or normal) but matched on VAT volume or differed in VAT volume (high or low) but matched on IHTG content. Stable isotope tracer techniques and the euglycemic–hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-low-density lipoprotein–triglyceride (VLDL-TG) secretion rate. Tissue biopsies were obtained to evaluate cellular factors involved in ectopic triglyceride accumulation. Hepatic, adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0.01), whereas VLDL-triglyceride secretion rate was almost double (P < 0.001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Adipose tissue CD36 expression was lower (P < 0.05), whereas skeletal muscle CD36 expression was higher (P < 0.05), in subjects with higher than normal IHTG. These data demonstrate that IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Furthermore, alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.

Leptin in human physiology and pathophysiology

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptins effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

Surgical Removal of Omental Fat Does Not Improve Insulin Sensitivity and Cardiovascular Risk Factors in Obese Adults

BACKGROUND & AIMS Visceral adipose tissue (VAT) is an important risk factor for the metabolic complications associated with obesity. Therefore, a reduction in VAT is considered an important target of obesity therapy. We evaluated whether reducing VAT mass by surgical removal of the omentum improves insulin sensitivity and metabolic function in obese patients. METHODS We conducted a 12-month randomized controlled trial to determine whether reducing VAT by omentectomy in 22 obese subjects increased their improvement following Roux-en-Y gastric bypass (RYGB) surgery in hepatic and skeletal muscle sensitivity to insulin study 1. Improvement was assessed by using the hyperinsulinemic-euglycemic clamp technique. We also performed a 3-month, longitudinal, single-arm study to determine whether laparoscopic omentectomy alone, in 7 obese subjects with type 2 diabetes mellitus (T2DM), improved insulin sensitivity study 2. Improvement was assessed by using the Frequently Sampled Intravenous Glucose Tolerance Test. RESULTS The greater omentum, which weighed 0.82 kg (95% confidence interval: 0.67-0.97), was removed from subjects who had omentectomy in both studies. In study 1, there was an approximate 2-fold increase in muscle insulin sensitivity (relative increase in glucose disposal during insulin infusion) and a 4-fold increase in hepatic insulin sensitivity 12 months after RYGB alone and RYGB plus omentectomy, compared with baseline values (P<.001). There were no significant differences between groups (P>.87) or group x time interactions (P>.36). In study 2, surgery had no effect on insulin sensitivity (P=.844) or use of diabetes medications. CONCLUSIONS These results demonstrate that decreasing VAT through omentectomy, alone or in combination with RYGB surgery, does not improve metabolic function in obese patients.

Association Between Specific Adipose Tissue CD4+ T-Cell Populations and Insulin Resistance in Obese Individuals

BACKGROUND & AIMS An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure. METHODS We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors. RESULTS Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes. CONCLUSIONS Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.

Intrahepatic Diacylglycerol Content Is Associated With Hepatic Insulin Resistance in Obese Subjects

Data from studies in animal models indicate that certain lipid metabolites, particularly diacylglycerol, ceramide, and acylcarnitine, disrupt insulin action. We evaluated the relationship between the presence of these metabolites in the liver (assessed by mass spectrometry) and hepatic insulin sensitivity (assessed using a hyperinsulinemic-euglycemic clamp with stable isotope tracer infusion) in 16 obese adults (body mass index, 48 ± 9 kg/m²). There was a negative correlation between insulin-mediated suppression of hepatic glucose production and intrahepatic diacylglycerol (r = -0.609; P = .012), but not with intrahepatic ceramide or acylcarnitine. These data indicate that intrahepatic diacylglycerol is an important mediator of hepatic insulin resistance in obese people with nonalcoholic fatty liver disease.

Relationship between body fat mass and free fatty acid kinetics in men and women

An increased release of free fatty acids (FFAs) into plasma likely contributes to the metabolic complications associated with obesity. However, the relationship between body fat and FFA metabolism is unclear because of conflicting results from different studies. The goal of our study was to determine the inter‐relationships between body fat, sex, and plasma FFA kinetics. We determined FFA rate of appearance (Ra) in plasma, by using stable isotopically labeled tracer techniques, during basal conditions in 106 lean, overweight, and obese, nondiabetic subjects (43 men and 63 women who had 7.0–56.0% body fat). Correlation analyses demonstrated: (i) no differences between men and women in the relationship between fat mass (FM) and total FFA Ra (µmol/min); (ii) total FFA Ra increased linearly with increasing FM (r = 0.652, P < 0.001); (iii) FFA Ra per kg FM decreased in a curvilinear fashion with increasing FM (r = −0.806; P < 0.001); (iv) FFA Ra in relationship to fat‐free mass (FFM) was greater in obese than lean subjects and greater in women than in men; and (v) abdominal fat itself was not an important determinant of total FFA Ra. We conclude that total body fat, not regional fat distribution or sex, is an important modulator of the rate of FFA release into plasma. Although increased adiposity is associated with a decrease in fatty acid release in relationship to FM, this downregulation is unable to completely compensate for the increase in FM, so total FFA Ra and FFA Ra with respect to FFM are greater in women than in men and in obese than in lean subjects.

Metabolic actions of insulin in men and women

Insulin is an important regulator of glucose, lipid, and protein metabolism. It suppresses hepatic glucose and triglyceride production, inhibits adipose tissue lipolysis and whole-body and muscle proteolysis, and stimulates glucose uptake in muscle. In this review we discuss what is currently known about the control of substrate metabolism by insulin in men and women. The data available so far indicate that women are more sensitive to insulin with regards to glucose metabolism (both in the liver and in muscle), whereas there are no differences between men and women in insulin action on lipolysis. Potential differences exist in the regulation of plasma triglyceride concentration and protein metabolism by insulin and in changes in insulin action in response to stimuli (e.g., weight loss and exercise) that are known to alter insulin sensitivity. However, these areas have not been studied comprehensively enough to draw firm conclusions.

Increased whole-body adiposity without a concomitant increase in liver fat is not associated with augmented metabolic dysfunction.

Aim of this study was to determine whether an increase in adiposity, without a concomitant increase in intrahepatic triglyceride (IHTG) content, is associated with a deterioration in metabolic function. To this end, multiorgan insulin sensitivity, assessed by using a two‐stage hyperinsulinemic–euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusion, and very low‐density lipoprotein (VLDL) kinetics, assessed by using stable isotopically labeled tracer infusion and mathematical modeling, were determined in 10 subjects with class I obesity (BMI: 31.6 ± 0.3 kg/m2; 37 ± 2% body fat; visceral adipose tissue (VAT): 1,225 ± 144 cm3) and 10 subjects with class III obesity (BMI: 41.5 ± 0.5 kg/m2; 43 ± 2% body fat; VAT: 2,121 ± 378 cm3), matched on age, sex, and IHTG content (14 ± 4 and 14 ± 3%, respectively). No differences between class I and class III obese groups were detected in insulin‐mediated suppression of palmitate (67 ± 3 and 65 ± 3%, respectively; P = 0.635) and glucose (67 ± 3 and 73 ± 5%, respectively; P = 0.348) rates of appearance in plasma, and the insulin‐mediated increase in glucose disposal (218 ± 18 and 193 ± 30%, respectively; P = 0.489). In addition, no differences between class I and class III obese groups were detected in secretion rates of VLDL‐triglyceride (6.5 ± 1.0 and 6.0 ± 1.4 µmol/l·min, respectively; P = 0.787) and VLDL‐apolipoprotein B‐100 (0.40 ± 0.05 and 0.41 ± 0.04 nmol/l·min, respectively; P = 0.866), and plasma clearance rates of VLDL‐triglyceride (31 (16–59) and 29 (18–46) ml/min, respectively; P = 0.888) and VLDL‐apolipoprotein B‐100 (15 (11–19) and 17 (11–25) ml/min, respectively; P = 0.608). We conclude that increased adiposity without a concomitant increase in IHTG content does not cause additional abnormalities in adipose tissue, skeletal muscle, and hepatic insulin sensitivity, or VLDL metabolism.

Effect of obesity on the plasma lipoprotein subclass profile in normoglycemic and normolipidemic men and women

Objective:To determine the effect of obesity without the confounding effect of metabolic complications on the lipoprotein subclass profile in men and women.Design:Cross-sectional study.Subjects:A total of 40 lean (body mass index (BMI): 18.5–25 kg/m2) and 40 obese (BMI: 30–45 kg/m2) subjects, with blood pressure <140/90 mm Hg, fasting plasma glucose concentration <100 mg per 100 ml and total triglyceride concentration <150 mg per 100 ml; all obese subjects had normal oral glucose tolerance.Measurements:Fasting concentrations of very low-, intermediate-, low- and high-density lipoproteins (VLDL, IDL, LDL, and HDL, respectively) and average VLDL, LDL and HDL particle sizes were evaluated by using proton nuclear magnetic resonance spectroscopy.Results:Obese compared with lean individuals of both sexes had increased plasma concentrations of VLDL (by ∼50%), IDL (by ∼100%), LDL (by ∼50%), and to some extent HDL (by ∼10%) particles (P<0.05). The contribution of large VLDL to total VLDL concentration, small LDL to total LDL concentration, and small HDL to total HDL concentration was greater in obese than lean subjects (P<0.05), resulting in larger average VLDL size but smaller average LDL and HDL sizes (P<0.05). Women, compared with men, had reduced concentrations of total VLDL particles (by ∼10%) due to lower concentrations of large and medium VLDL and a shift toward large at the expense of small HDL particles (P<0.05), with no difference in total HDL particle concentration. IDL and total LDL concentrations and LDL subclass distribution were not different between men and women.Conclusion:Obesity is associated with pro-atherogenic alterations in the lipoprotein subclass profile, which may increase cardiovascular disease risk even in the absence of classical metabolic risk factors. On the other hand, the female cardiovascular disease risk advantage is probably largely related to differences in traditional lipid risk factors (plasma triglyceride and HDL-cholesterol concentrations) because sex differences in the plasma lipoprotein subclass profile are minimal.

Effect of Roux-en-Y Gastric Bypass and Laparoscopic Adjustable Gastric Banding on Branched-Chain Amino Acid Metabolism

It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, possibly by decreased signaling through the mammalian target of rapamycin (mTOR). We evaluated plasma BCAAs and their C3 and C5 acylcarnitine metabolites, muscle mTOR phosphorylation, and insulin sensitivity (insulin-stimulated glucose Rd) in obese subjects before and after ∼20% weight loss induced by RYGB (n = 10, BMI 45.6 ± 6.7 kg/m2) or laparoscopic adjustable gastric banding (LAGB) (n = 10, BMI 46.5 ± 8.8 kg/m2). Weight loss increased insulin-stimulated glucose Rd by ∼55%, decreased total plasma BCAA and C3 and C5 acylcarnitine concentrations by 20–35%, and did not alter mTOR phosphorylation; no differences were detected between surgical groups (all P values for interaction >0.05). Insulin-stimulated glucose Rd correlated negatively with plasma BCAAs and with C3 and C5 acylcarnitine concentrations (r values −0.56 to −0.75, P < 0.05). These data demonstrate that weight loss induced by either LAGB or RYGB causes the same decline in circulating BCAAs and their C3 and C5 acylcarnitine metabolites. Plasma BCAA concentration is negatively associated with skeletal muscle insulin sensitivity, but the mechanism(s) responsible for this relationship is not known.