Adipocytokines and the Regulation of Lipid Metabolism in Growth Hormone Transgenic and Calorie-Restricted Mice

Abstract

Chronic elevation of GH induces resistance to insulin and hyperinsulinemia in both humans and animals, whereas calorie restriction (CR) improves peripheral insulin sensitivity in many species. To investigate the mechanisms that lead to insulin resistance in animals with high levels of GH as well as the mechanisms that might improve insulin sensitivity, we fed GH-overexpressing transgenic mice ad libitum or subjected them to 30% CR. We then assayed the plasma adipocytokines levels related to insulin sensitivity, plasma lipid levels, and tissue triglycerides accumulation and examined adipocyte morphology. Furthermore, we evaluated mRNA expression and protein levels of enzymes or regulators involved in regulating hepatic lipid metabolism. Our results suggest that decreased plasma adiponectin, increased plasma resistin and cholesterol, and elevated levels of TNF-alpha and IL-6 in adipocytes may all contribute to the insulin resistance observed in GH-Tg mice. Increased accumulation of triglycerides and impaired adipocytes differentiation in GH-transgenic mice provide plausible mechanisms for the alterations of adipocytokines. Hepatic and muscle insulin resistance in these mice is probably related to excessive accumulation of fatty acids and their metabolites. An increase in plasma adiponectin and decrease in plasma IL-6, triglycerides, and cholesterol levels in response to CR may improve insulin sensitivity.

DLK1/PREF1 regulates nutrient metabolism and protects from steatosis

“…FA synthesis, clearance, and release are regulated by neuroendocrine factors including GH, whose levels vary under conditions of changing energy supply (2). Recent animal studies have underscored the important role of hepatic GH signaling in the development of NAFLD and the metabolic syndrome (3)(4)(5)(6).…”

Overexpression of the adiponectin gene mimics the metabolic and stress resistance effects of calorie restriction, but not the anti-tumor effect

“…However, 16-months' CR does not significantly increase the plasma concentration or the mRNA level of Adipoq in the epididymal fat tissue (Wang, 2006). A 25% CR regimen using a diet formulated to be isocaloric with the control diet (American Institute Nutrition (AIN)-93M diet) with 25% increases in protein, vitamin, mineral and fat content did not elevate the plasma Adipoq concentration in mice of a mammary tumor model during a 64-week-long experiment (Dogan, 2010).…”

Estrogens in the Control of Growth Hormone Actions in Liver

“…GH treatment promotes a state of intrahepatic triglyceride storage. Several studies in bGHtransgenic mice, defficient GHR-JAK2-STAT-5 signaling pathway, GH-treated intact or GHdeficient rats (hypophysectomized or hypothyroid), as well as experiments in PPAR null mice, have all revealed that GH down-regulates genes involved in lipid oxidation and increases the expression of genes promoting lipogenesis in the liver (Olsson et al, 2003;Wang et al, 2007;Barclay et al, 2011;Sos et al, 2011). On the other hand, an impaired GHR-JAK2-STAT-5 signaling strongly correlates with hepatic steatosis (Fan et al, 2009;Barclay et al, 2011;Sos et al, 2011).…”