GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle

Abstract

Obesity is associated with insulin resistance in skeletal muscle; accordingly, weight loss dramatically improves insulin action. We sought to identify molecular remodeling of muscle commensurate with weight loss that could explain improvements in insulin action. Muscle from morbidly obese women was studied before and after gastric bypass surgery. Gastric bypass surgery significantly reduced body mass by approximately 45% and improved insulin action. We then assessed mRNA profiles using a stringent statistical analysis (statistical concordance with three probe set algorithms), with validation in a cross-sectional study of lean (n = 8) vs. morbidly obese (n = 8) muscle. Growth factor receptor-bound protein 14 (GRB14), glycerol-3-phosphate dehydrogenase 1 (GPD1), and growth differentiation factor 8 (GDF8; myostatin) significantly decreased approximately 2.4-, 2.2-, and 2.4-fold, respectively, after weight loss (gastric bypass). Increased expression of these transcripts was associated with increased obesity in the cross-sectional group (lean vs. morbidly obese muscle). Each transcript was validated by real-time quantitative RT-PCR assays in both study groups. Using Ingenuity Pathway Analysis, we show that all three transcripts are involved in the same regulatory network including AKT1, IGF1, TNF, PPARG, and INS. These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss. Thus our data provide a possible regulatory pathway involved in the development of insulin resistance in the morbidly obese state, and improvement of insulin resistance with weight loss.

Building muscle, browning fat and preventing obesity by inhibiting myostatin

“…Increased circulating levels of myostatin in this cohort were found to be correlated with insulin resistance [24]. In addition, the expression of the gene encoding myostatin (MSTN) in skeletal muscle of obese patients undergoing gastric bypass surgery was significantly decreased in response to weight loss and associated with improved insulin action [25,26]. Increased expression of MSTN was also recently detected in skeletal muscle biopsies of healthy but at risk first-degree relatives of patients with type 2 diabetes mellitus [27].…”

Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women

“…Recent studies, however, have shown that myostatin inhibits glucose uptake in placental cell lines, suggesting that it may contribute to systemic insulin resistance with obesity (35). Others have implicated myostatin in a network of genes potentially regulated by insulin with extreme obesity (30). Severe caloric restriction and starvation have also been shown to increase myostatin expression in skeletal muscle, presumably to reduce the metabolic burden of a large muscle mass (36).…”

“…This may contribute to systemic metabolic deterioration of skeletal muscle with the progression of insulin resistance to type 2 diabetes. Diabetes 58: [30][31][32][33][34][35][36][37][38] 2009 O besity and type 2 diabetes are associated with endocrine abnormalities that are either precipitated by or precede the onset of peripheral insulin resistance (1). These include changes in circulating proteins and peptides that produce endothelial dysfunction, low-grade inflammation, and a prothrombotic state, all of which contribute to increased cardiovascular risk (2-4).…”

Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery

“…Several studies have demonstrated changes in genes associated with insulin action after bariatric operations (17,18). In previous studies, we demonstrated that the prevalence of obesity in children born after maternal bypass surgery (AMS) was significantly lower than in siblings born before maternal surgery (BMS) (19) and was associated with greater insulin sensitivity, less adiposity, hypertension, and dyslipidemia compared with BMS offspring, suggesting that these improvements in cardiometabolic markers may be attributable to an improved intrauterine environment (20).…”