Adewole L. Okunade

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.

Gastric bypass and banding equally improve insulin sensitivity and β cell function

Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide-1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.

Ageratum conyzoides L. (Asteraceae)

Ageratum conyzoides L., is an annual herb with a long history of traditional medicinal uses in many countries in the world, especially in the tropical and subtropical regions. A wide range of chemical compounds including alkaloids, flavonoids, chromenes, benzofurans and terpenoids have been isolated from this species. Extracts and metabolites from this plant have been found to possess pharmacological and insecticidal activities. The comprehensive account of the chemical constituents and the biological activities are presented in this review such that the potential use of this plant either in pharmaceutics or as an agricultural resource can be evaluated.

WNT-LRP5 Signaling Induces Warburg Effect through mTORC2 Activation during Osteoblast Differentiation

WNT signaling controls many biological processes including cell differentiation in metazoans. However, how WNT reprograms cell identity is not well understood. We have investigated the potential role of cellular metabolism in WNT-induced osteoblast differentiation. WNT3A induces aerobic glycolysis known as Warburg effect by increasing the level of key glycolytic enzymes. The metabolic regulation requires LRP5 but not β-catenin and is mediated by mTORC2-AKT signaling downstream of RAC1. Suppressing WNT3A-induced metabolic enzymes impairs osteoblast differentiation in vitro. Deletion of Lrp5 in the mouse, which decreases postnatal bone mass, reduces mTORC2 activity and glycolytic enzymes in bone cells and lowers serum lactate levels. Conversely, mice expressing a mutant Lrp5 that causes high bone mass exhibit increased glycolysis in bone. Thus, WNT-LRP5 signaling promotes bone formation in part through direct reprogramming of glucose metabolism. Moreover, regulation of cellular metabolism may represent a general mechanism contributing to the wide-ranging functions of WNT proteins.

The brown fat–enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis

Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat–enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).

Role of Fat Body Lipogenesis in Protection against the Effects of Caloric Overload in Drosophila

Background: A high sugar diet leads to obesity and insulin resistance in Drosophila. Results: The metabolic fate of dietary glucose is reprogrammed in high sugar-fed and lean animals. Conclusion: Obesity is protective against the deleterious effects of a high sugar diet. Significance: An emerging perspective that obesity is protective against sequelae of human metabolic disease is conserved in the fly. The Drosophila fat body is a liver- and adipose-like tissue that stores fat and serves as a detoxifying and immune responsive organ. We have previously shown that a high sugar diet leads to elevated hemolymph glucose and systemic insulin resistance in developing larvae and adults. Here, we used stable isotope tracer feeding to demonstrate that rearing larvae on high sugar diets impaired the synthesis of esterified fatty acids from dietary glucose. Fat body lipid profiling revealed changes in both carbon chain length and degree of unsaturation of fatty acid substituents, particularly in stored triglycerides. We tested the role of the fat body in larval tolerance of caloric excess. Our experiments demonstrated that lipogenesis was necessary for animals to tolerate high sugar feeding as tissue-specific loss of orthologs of carbohydrate response element-binding protein or stearoyl-CoA desaturase 1 resulted in lethality on high sugar diets. By contrast, increasing the fat content of the fat body by knockdown of king-tubby was associated with reduced hyperglycemia and improved growth and tolerance of high sugar diets. Our work supports a critical role for the fat body and the Drosophila carbohydrate response element-binding protein ortholog in metabolic homeostasis in Drosophila.

Increased glutamine catabolism mediates bone anabolism in response to WNT signaling

WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2-mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were β-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases.

Insulin sensitivity is not associated with palmitoleate availability in obese humans

We evaluated whether insulin resistance in obese people is associated with decreased plasma palmitoleate availability. Palmitoleate content (percentage and absolute concentrations) in FFA and VLDL was measured in obese subjects who were either insulin resistant (IR) or insulin sensitive (IS), based on assessment of multiorgan (skeletal muscle, liver, and adipose tissue) insulin sensitivity by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with infusion of stable isotopically labeled tracers. Plasma palmitoleate concentration and the relative contribution of palmitoleate to total plasma FFA concentration in the IS group (0.018 ± 0.002 mmol/l and 4.4% ± 0.2%, respectively) were not significantly different than values in the IR group (0.023 ± 0.003 mmol/l and 4.4% ± 0.4%, respectively). Plasma VLDL-triglyceride palmitoleate concentration and the proportion of VLDL fatty acids as palmitoleate in the IS group (0.09 ± 0.02 mmol/l and 5.7 ± 0.3%, respectively) were also not significantly different than those in the IR group (0.16 ± 0.04 mmol/l and 5.0% ± 0.4%, respectively). These data demonstrate that decreased palmitoleate in plasma and in VLDL is not associated with insulin resistance in skeletal muscle, liver, or adipose tissue in obese people.

Ginseng and Ginsenoside Re Do Not Improve β-Cell Function or Insulin Sensitivity in Overweight and Obese Subjects With Impaired Glucose Tolerance or Diabetes

OBJECTIVE Ginseng and its active component, ginsenoside Re, are popular herbal products that are advocated for treatment of diabetes. The purpose of this study was to determine whether ginseng or ginsenoside Re improves β-cell function and insulin sensitivity (IS) in insulin-resistant subjects. RESEARCH DESIGN AND METHODS Overweight or obese subjects (BMI = 34 ± 1 kg/m2) with impaired glucose tolerance or newly diagnosed type 2 diabetes were randomized to 30 days of treatment with ginseng root extract (8 g/day), ginsenoside Re (250–500 mg/day), or placebo. β-Cell function was assessed as the disposition index (DI) and measured by a frequently sampled oral glucose tolerance test, and IS was assessed as the relative increase in glucose disposal during a hyperinsulinemic-euglycemic clamp procedure plus stable isotope tracer infusion. RESULTS Values for DI and IS after therapy (Post) were not different from values before therapy (Pre) in the placebo (DI: Pre, 5.8 ± 0.9 × 10−3 and Post, 5.8 ± 0.8 × 10−3, P = 0.99; IS: Pre,165 ± 29% and Post, 185 ± 24%, P = 0.34), ginseng (DI: Pre, 7.7 ± 2.0 × 10−3 and Post, 6.0 ± 0.8 × 10−3, P = 0.29; IS: Pre, 171 ± 72% and Post,137 ± 59%, P = 0.88), and ginsenoside Re (DI: Pre, 7.4 ± 3.0 × 10−3 and Post, 5.9 ± 1.1 × 10−3, P = 0.50; IS: Pre, 117 ± 31% and Post, 134 ± 34%, P = 0.44) groups. Ginsenosides Re, Rb1, and Rb2 were not detectable in plasma after treatment with ginseng root extract or ginsenoside Re. CONCLUSIONS Oral ginseng or ginsenoside Re therapy does not improve β-cell function or IS in overweight/obese subjects with impaired glucose tolerance or newly diagnosed diabetes. Poor systemic bioavailability might be responsible for the absence of a therapeutic effect.

CD36 level and trafficking are determinants of lipolysis in adipocytes

CD36 has been linked to the etiology of insulin resistance and inflammation. We explored its function in regulating adipose tissue lipolysis, which influences fat accumulation by liver and muscle and overall metabolism. Knockdown of CD36 in differentiated 3T3‐L1 adipocytes decreased lipolysis in response to 10 μM of the β‐adrenergic agonist isoproterenol (by 42%), 10 μM of the adenyl cyclase activator forskolin (by 32%), and 500 μM of the phosphodiesterase (PDE) inhibitor isobutylmethylxanthine (by 33%). All three treatments in the knockdown adipocytes were associated with significant decreases of cAMP levels and of the hormone‐sensitive lipase (HSL) and perilipin phosphorylation. An important role for PDE was supported by the lack of inhibition of the lipolysis induced by the poorly hydrolyzable dibutyryl cAMP analog. An additional contributory mechanism was diminished activation of the Src‐ERK1/2 pathway. Regulation of lipolysis and lipolytic signaling by CD36 was reproduced with adipose tissue from CD36–/– mice. The importance of surface CD36 in this regulation was suggested by the finding that the plasma membrane‐impermeable CD36 inhibitor sulfo‐N‐succinimidyl oleate (20 μM) decreased lipolysis. Interestingly, isoproterenol induced CD36 internalization, and this process was blocked by HSL inhibition, suggesting feedback regulation of adipocyte lipolysis via CD36 trafficking.—Zhou, D., Samovski, D., Okunade, A. L., Stahl, P. D., Abumrad, N. A., Su, X., CD36 level and trafficking are determinants of lipolysis in adipocytes. FASEB J. 26, 4733–4742 (2012). www.fasebj.org