Gene expression in skeletal muscle after an acute intravenous GH bolus in human subjects: identification of a mechanism regulating ANGPTL4.

Growth hormone (GH) acutely stimulates lipolysis and fat oxidation, a process that operates postabsorptively and involves activation of the JAK-STAT pathway in the target tissue; no in vivo data exist regarding subsequent GH-regulated gene transcription. We obtained serum samples and muscle biopsies in human subjects before and 2 h after administration of a GH bolus. A significant (~75%) elevation in serum FFA levels was recorded post GH. Microarray identified 79 GH-regulated genes in muscle. With qRT-PCR, we then examined the expression of selected genes in the presence and absence of glucose-induced suppression of lipolysis. Four genes involved in the JAK-STAT5 signaling pathway were regulated by GH, including SOCS1-3 and CISH, in addition to three genes associated with insulin action: NFκB1A, PIK3C2B, and PRKAG2. The gene encoding ANGPTL4, a protein involved in lipolysis and suppression of LPL activity, exhibited the most pronounced upregulation (5.6-fold) after GH, which was abrogated by concomitant suppression of lipolysis. Therefore, the GH-induced stimulation of ANGPTL4 gene expression seems secondary to induction of lipolysis. This new concept implies that abundant supply of circulating FFA decreases the need for alternative triglyceride-derived FFA through distinct inhibition of LPL mediated by increased ANGPTL4 gene expression in human muscle.

Effects of GH in human muscle and fat.

Skeletal muscle is the major constituent of lean body mass and a major determinant of energy expenditure both at rest and during physical activity. Growth hormone, in turn, influences muscle mass as well as energy expenditure. Growth hormone substitution in adults increases muscle mass by 5-10%, but part of the effect is attributed to rehydration rather than protein accretion. In addition, GH regulates substrate metabolism in muscle and in particular antagonizes insulin-stimulated glucose disposal. This effect is linked to increased free fatty acid (FFA) flux but the molecular mechanisms remain unclear. During fasting, GH-induced insulin resistance may be favorable by reducing the demand of gluconeogenesis from protein. But in the postprandial phase, GH exposure may compromise glucose tolerance via the same mechanisms. Understanding the mechanisms whereby GH antagonizes insulin-stimulated glucose disposal in muscle is an important future research field with implications for a variety of clinical conditions ranging from malnutrition to obesity and type 2 diabetes.