This Month in Gastroenterology

The rise in obesity-related morbidity in children and adolescents requires urgent prevention and treatment strategies. Currently, only limited data are available on the effects of exercise programs on insulin resistance, and visceral, hepatic, and intramyocellular fat accumulation. We hypothesized that a 12-week controlled aerobic exercise program without weight loss reduces visceral, hepatic, and intramyocellular fat content and decreases insulin resistance in sedentary Hispanic adolescents. Twenty-nine postpubertal (Tanner stage IV and V), Hispanic adolescents, 15 obese (7 boys, 8 girls; 15.6 +/- 0.4 years; 33.7 +/- 1.1 kg/m(2); 38.3 +/- 1.5% body fat) and 14 lean (10 boys, 4 girls; 15.1 +/- 0.3 years; 20.6 +/- 0.8 kg/m(2); 18.9 +/- 1.5% body fat), completed a 12-week aerobic exercise program (4 x 30 min/week at > or =70% of peak oxygen consumption (VO(2)peak)). Measurements of cardiovascular fitness, visceral, hepatic, and intramyocellular fat content (magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS)), and insulin resistance were obtained at baseline and postexercise. In both groups, fitness increased (obese: 13 +/- 2%, lean: 16 +/- 4%; both P < 0.01). In obese participants, intramyocellular fat remained unchanged, whereas hepatic fat content decreased from 8.9 +/- 3.2 to 5.6 +/- 1.8%; P < 0.05 and visceral fat content from 54.7 +/- 6.0 to 49.6 +/- 5.5 cm(2); P < 0.05. Insulin resistance decreased indicated by decreased fasting insulin (21.8 +/- 2.7 to 18.2 +/- 2.4 microU/ml; P < 0.01) and homeostasis model assessment of insulin resistance (HOMA(IR)) (4.9 +/- 0.7 to 4.1 +/- 0.6; P < 0.01). The decrease in visceral fat correlated with the decrease in fasting insulin (R(2) = 0.40; P < 0.05). No significant changes were observed in any parameter in lean participants except a small increase in lean body mass (LBM). Thus, a controlled aerobic exercise program, without weight loss, reduced hepatic and visceral fat accumulation, and decreased insulin resistance in obese adolescents.

Bone Marrow–Derived Hepatic Oval Cells Differentiate Into Hepatocytes in 2-Acetylaminofluorene/Partial Hepatectomy–Induced Liver Regeneration

Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity. We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content. Thirty-four healthy obese subjects (body mass index, 33.7 +/- 8.0 kg/m(2)) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [(18)F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [(18)F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy. Subjects lost weight (11.2 +/- 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), which was partly explained by decreased liver fat content (P < 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrement in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05). The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.

Hepatic fat is related to insulin resistance (IR) and visceral adipose tissue (VAT) in HIV+ and uninfected individuals. Growth hormone (GH) reduces VAT but increases IR. We evaluated the effects of recombinant human GH (rhGH) and rosiglitazone (Rosi) on hepatic fat in a substudy of a randomized controlled trial. HIV+ subjects with abdominal obesity and IR (QUICKI≤0.33) were randomized to rhGH 3 mg daily, Rosi 4 mg twice daily, the combination or double placebo. Hepatic fat was measured by magnetic resonance spectroscopy, visceral fat by MRI and IR by frequently sampled intravenous glucose tolerance tests at baseline and week 12. 31 subjects were studied at both time points. Significant correlations between hepatic fat and VAT (r=0.41; P=0.02) and QUICKI (r=0.39; P<0.05) were seen at baseline. IR rose with rhGH but not Rosi. When rhGH treatment groups were combined, hepatic fat expressed as percentage change decreased significantly (P<0.05) but did not change in Rosi (P=0.71). There were no correlations between changes in hepatic fat and VAT (P=0.4) or QUICKI (P=0.6). In a substudy of 21 subjects, a trend was noticed between changes in hepatic fat and serum insulin-like growth factor-1 (IGF-1; P=0.09). Hepatic fat correlates significantly with both VAT and IR, but changes in hepatic fat do not correlate with changes in VAT and glucose metabolism. Hepatic fat content is reduced by rhGH but Rosi has no effect. These results suggest an independent effect of GH or IGF-1 on hepatic fat. The study was registered at Clinicaltrials.gov (NCT00130286).

BackgroundObesity‐associated metabolic disorders have been shown to be related to body fat distribution. Specifically, increases in visceral fat are more detrimental than increases in subcutaneous fat depots. However, the underlying mechanisms through which visceral fat potentiates cardiometabolic dysregulation are not completely understood. In recent years, the presence of localized renin angiotensin system (RAS) in adipose tissue and its role in regulating blood pressure and metabolism has been recognized. Therefore, we investigated if differential expression of RAS components in visceral versus subcutaneous adipose tissue may help explain pathological effects of visceral fat.HypothesisWe hypothesized that compared to subcutaneous adipose tissue, visceral adipose tissue has increased expression of RAS proteins involved in the pro‐inflammatory and pro‐fibrotic ANGII‐AT1R pathway but attenuated expression of proteins mediating the anti‐inflammatory and anti‐fibrotic ANG1‐7‐MASR pathway.MethodsWe determined the expression of RAS proteins in paired subcutaneous and visceral (omental) adipose tissue samples from obese individuals undergoing surgery (n = 30, BMI: 46.1 ± 7.3 kg/m2, age: 46.5 ± 14.4 years) by Western blot. We examined proteins involved in 1) Ang II generation: angiotensinogen (AGT), angiotensin converting enzyme (ACE), chymase; 2) Ang1‐7 generation: ACE‐2; and 3) cellular receptors: angiotensin I receptor (AT1R), MAS receptor (MASR), and aldosterone receptor.ResultsComparison of protein expression between subcutaneous and visceral adipose tissue samples showed no changes in proteins involved in generation of angiotensin peptides, namely AGT (0.64 ± 0.57 vs. 0.33 ± 0.28, p = 0.11, n = 12), chymase (0.27 ± 0.23 vs. 0.36 ± 0.41, p = 0.77, n = 22), and ACE‐2 (0.23 ± 0.41 vs. 0.08 ± 0.09, p = 0.21, n = 15). However, ACE expression tended to be higher in subcutaneous vs. visceral fat (0.10 ± 0.06 vs. 0.06 ± 0.03, p = 0.052, n = 12). Furthermore, expression of cellular receptor AT1R was higher in subcutaneous fat (0.24 ± 0.34 vs. 0.07 ± 0.09, p = 0.03, n = 12), and MASR was lower in subcutaneous fat (0.22 ± 0.26 vs. 0.88 ± 0.99, p = 0.01, n = 20). Aldosterone receptor expression (0.21 ± 0.22 vs. 0.14 ± 0.13, p = 0.52, n = 11) was not altered in subcutaneous and visceral depots.ConclusionsProteins involved in the generation of angiotensin peptides are not differentially expressed in subcutaneous versus visceral fat depots. However, expression of cellular receptors is different such that inflammatory and fibrotic effects of RAS may be more predominant in subcutaneous fat. Therefore, RAS is likely to play a role in limiting subcutaneous fat expansion thereby leading to increased visceral fat depots. Furthermore, our findings do not support the role of visceral RAS in development and progression of cardiovascular pathology associated with increased visceral fat depots.Support or Funding InformationMAP and KRS were supported by the American Physiological Society Stride Summer Undergraduate Research Fellowship NHLBI 1 R25 HL115473‐01.

Effects of 4 weight-loss diets differing in fat, protein, and carbohydrate on fat mass, lean mass, visceral adipose tissue, and hepatic fat: results from the POUNDS LOST trial

In black women, triglycerides (TG) are paradoxically normal in the presence of insulin resistance (IR). This TG paradox while partially explained by low visceral fat, might be further clarified by delineating the association of triglyceride rich lipoprotein (TRLP) subclasses with hepatic fat, IR and stearoyl-CoA enzyme activity (SCD-116, a marker of de novo lipogenesis). We hypothesized that fasting TRLP, hepatic fat and SCD-116 activity would be lower in black vs. white women. In 122 federally employed women without diabetes, we compared fasting TRLP number and size (measured with NMR) in 73 black (58 African American and 15 African immigrant) and 49 white; age 44±10 (mean±SD), range 24- 62y; BMI 30.0±5.6, range 20.3-45.2 kg/m2. Hepatic and visceral fat were measured by proton MRS. RBC fatty acid profiles were measured by gas chromatography (mol %) and used to estimate SCD-116 (16:1n-7/to 16:0). Total, large, medium and small TRLPs, visceral fat, SCD-116 were similar in blacks and lower than in whites before and after adjustment for age and body fat (P&amp;lt;0.001). Blacks had lower SI (2.28 (1.52) vs. 2.74 (2.81), median(IQR) P=0.05, and hepatic fat (0.7 (1.1) vs. 1.2 (2.1), P=0.03. SCD-116 correlated with hepatic fat (r=0.34, P&amp;lt;0.01). Habitual physical activity, dietary fatty acid profiles were similar (P&amp;gt;0.1). In multivariate linear models, age, SCD-116, body fat, visceral fat and SI, but not race or liver fat, were independently associated with total TRLP (adjR2=0.44, P&amp;lt;0.01). Medium and large TRLP number was independently predicted by visceral fat and SCD-116 activity (adjR2=0.37, P&amp;lt;0.01); race was the only predictor for small TRLPs (adjR2=0.14, P&amp;lt;0.01). Therefore, lower hepatic fat and SCD-116 maybe important contributors to the paradoxically normal fasting TRLP in insulin resistant black women. Disclosure S.T. Chung: None. M. Galvan-De La Cruz: None. S. Bernstein: None. A. Onuzuruike: None. N.R. Matthan: None. R. Ouwerkerk: None. L. Mabundo: None. M.L. Sampson: None. A.B. Courville: None. A.M. Gharib: None. A.H. Lichtenstein: None. A. Remaley: None. A.E. Sumner: None.

There is a high prevalence of type 2 diabetes mellitus and coronary artery disease among urban and migrant Asian Indians despite the absence of traditional risk factors. Evidence exists that Asian Indians are more hyperinsulinemic than Caucasians and that hyperinsulinemia may be important in the development of these diseases. To test whether insulin action was related to total or regional adiposity and to explore the potential role of plasma leptin and lipids, we measured insulin-mediated glucose disposal by the euglycemic insulin clamp, adipose distribution and muscle volume using computed axial tomography, and fasting serum leptin and lipid levels in 20 healthy Asian Indian male volunteers (age, 36 +/- 10 yr). A mean body mass index of 24.5 +/- 2.5 kg/m2 was associated with an unusually high percentage of body fat (33 +/- 7%). The majority of the fat was sc, and 16% was visceral (intraabdominal) adipose tissue. The majority (66%) of these nonobese men were insulin resistant. The mean fasting serum leptin level was 7.6 +/- 3.3 ng/mL. Insulin action was inversely correlated with visceral adipose tissue, not total or abdominal sc adipose tissue. In contrast, leptin levels correlated with sc and total (not visceral) adipose tissue. Serum triglyceride and high density lipoprotein cholesterol levels were inversely correlated with each other and were directly related to insulin resistance and visceral (not subcutaneous) fat. Increased visceral fat in Asian Indians is associated with increased generalized obesity, which is not apparent from their nonobese body mass index. Increased visceral fat is related to dyslipidemia and increased frequency of insulin resistance and may account for the increased prevalence of diabetes mellitus and cardiovascular disease in Asian Indians.

Ethnic differences in lipoprotein subclasses in obese adolescents: importance of liver and intraabdominal fat accretion

Visceral and subcutaneous adipose tissue, which one induced thyroid dysfunction in patients with morbid obesity.

Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance. CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI) >40 kg m(-2)), who underwent laparoscopic surgery for gastric banding (n=20), matched for age and sex to controls (BMI<30 kg m(-2); n=20) was analyzed. CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P=0.024). Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

The Effects of Dietary Soybean Oil on Liver Fat and Visceral Adipose Tissue in Adults With Nonalcoholic Fatty Liver Disease: Study Protocol for a Randomized Control Trial

Regional distribution of adipose tissue is an important factor in conferring cardiometabolic risk and obesity-related morbidity. We tested the hypothesis that human visceral adipose tissue (VAT) impairs glucose homeostasis, whereas subcutaneous glutealfemoral adipose tissue (GFAT) protects against the development of impaired glucose homeostasis in mice. VAT and GFAT were collected from patients undergoing bariatric surgery and grafted onto the epididymal adipose tissue of weight- and age-matched severe, combined immunodeficient mice. SHAM mice underwent surgery without transplant of tissue. Mice were fed a high-fat diet after xenograft. Energy homeostasis, glucose metabolism, and insulin sensitivity were assessed 6 wk later. Xenograft of human adipose tissues was successful, as determined by histology, immunohistochemical evaluation of collagen deposition and angiogenesis, and maintenance of lipolytic function. Adipose tissue transplant did not affect energy expenditure, food intake, whole body substrate partitioning, or plasma free fatty acid, triglyceride, and insulin levels. Fasting blood glucose was significantly reduced in GFAT and VAT compared with SHAM, whereas glucose tolerance was improved only in mice transplanted with VAT compared with SHAM mice. This improvement was not associated with differences in whole body insulin sensitivity or plasma insulin between groups. Together, these data suggest that VAT improves glycemic control and GFAT does not protect against the development of high-fat diet-induced glucose intolerance. Hence, the intrinsic properties of VAT and GFAT do not necessarily explain the postulated negative and positive effects of these adipose tissue depots on metabolic health.

What is already known about this subject • Investigations of non-alcoholic fatty liver disease (NAFLD) by non-invasive imaging procedures have limited evidence. • Thirty percent of obese children are estimated to have NAFLD and implications for future morbidity are uncertain. What this study adds • Many obese children and youths exhibit a high liver fat content as examined by magnetic resonance spectroscopy. • Associations between liver fat content, anthropometry, abdominal adipose tissue distribution and liver enzymes are illustrated. The study aims to investigate the degree of hepatic steatosis and associations with the amount of abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), anthropometric data and biochemical measures of liver enzymes in children and youths included in obesity treatment. The study included 164 patients, aged 6-20 years, with a body mass index (BMI) above the 90th percentile for sex and age. Liver fat content was measured by magnetic resonance spectroscopy (MRS). SAT and VAT were measured by magnetic resonance imaging. Hepatic steatosis was defined as liver fat content >5% (steatosis-5%) and 9% (steatosis-9%), respectively. Data on waist circumference (WC) and blood samples were available in 124 patients. Steatosis-5% and steatosis-9% were identified in 45% and 27% of the patients, respectively. These patients had increased SAT, VAT, BMI standard deviation score, WC/height ratio, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels. GGT, ALT and VAT were found to be independent risk factors of hepatic steatosis. In this study, a substantial proportion of obese children and youths have hepatic steatosis. Therefore, it is important to examine these subjects for the degree of fat in their liver. Future studies focusing on hepatic steatosis should consider the use of MRS in addition to blood samples.

Moderate weight loss is recommended for overweight and obese patients with type 2 diabetes, and conjunctive use of weight loss medication has been advocated. The current study examined weight loss-dependent and -independent effects of the intestinal lipase inhibitor orlistat at 6 months of treatment, using behavioral intervention (Int) combined with randomized, double-blinded, placebo (P)-controlled treatment with orlistat (O). Metabolic control, insulin sensitivity (IS), regional fat distribution, and fat content in liver and muscle were measured in 39 volunteers with type 2 diabetes in whom all antidiabetic medication was withdrawn 1 month preceding randomization. Weight loss was equivalent in the Int+O and Int+P groups, respectively (-10.3 +/- 1.3 vs. -8.9 +/- 1.1%), and there were identical decreases in visceral adipose tissue (VAT), fat mass (FM), thigh adiposity, and hepatic steatosis. Weight loss resulted in substantial improvement (P < 0.001) in HbA(1c) (-1.6 +/- 0.3 vs. -1.0 +/- 0.4%; NS between groups). IS improved significantly more with orlistat (Delta2.2 +/- 0.4 vs. Delta1.2 +/- 0.4 mg. min(-1). kg(-1) fat-free mass [FFM]; P < 0.05), and plasma free fatty acid (FFA) levels were strongly correlated with IS (r = 0.56; P < 0.001). Orlistat caused greater reductions in fasting plasma FFA (Delta-154 +/- 22 vs. Delta-51 +/- 33 micro mol/l; P < 0.05), insulin-suppressed FFA (Delta-119 +/- 23 vs. Delta-87 +/- 34 micro mol/l; P < 0.05), and fasting plasma glucose (FPG; -62 +/- 9 vs. -32 +/- 8 mg/dl; P = 0.02). Changes in HbA(1c) were correlated with DeltaIS (r = -0.41; P < 0.01) but not with weight loss per se. At equivalent weight loss, conjunctive use of orlistat resulted in greater improvement in FFA levels and IS.