Growth Hormone Regulation of p85α Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Abstract

Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85␣ regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85␣ levels are associated with insulin resistance through PI 3-kinase-dependent and -independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85␣ subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85␣ mRNA and protein expression and insulin receptor substrate (IRS)-1-associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85␣ protein abundance. We found that p85␣ expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulininduced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85␣ expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess. Diabetes

Inflammatory adipokines contribute to insulin resistance in active acromegaly and respond differently to different treatment modalities

“…The increased FFAs may affect insulin sensitivity by competition with glucose for substrate oxidation, impairment of insulin signaling, altering b-cell function, or triggering monocyte-macrophage accumulation in adipose tissue (2,4,5). Further, GH directly alters the insulin signal cascade activity in mice, but studies on humans have not supported these observations (6,7,8). Data regarding the effects of GH on circulating adipokines in human subjects are sparse and the results often contrast those obtained from animal models (9).…”

Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes

“…The specific mechanisms responsible for insulin resistance caused by growth hormone remain unknown. While some recent findings suggest that phosphoinositide 3-kinase plays a pivotal role [29,30], others argue against this [27,28]. Obesity can also lead to an insulin-resistant state; thus, one might expect that growth hormone treatment of obese mice would exacerbate insulin resistance.…”

Diabetes and pancreatic cancer

“…Hyperglycemia was observed in some patients enrolled in studies with an anti-IGF1R antibody (Haluska et al 2006, Lacy et al 2008. This is likely to be a consequence of a compensatory increase in the circulating concentration of GH after IGF1 blockade, with the consequent increase in GH-induced insulin resistance (del Rincon et al 2007). Hyperglycemia, hypertriglyceridemia, and hypercholesterolemia were also observed in about 20% of patients treated with the mTOR inhibitors (Bellmunt et al 2008).…”