Effect of growth hormone on insulin signaling

Abstract

Growth hormone (GH) is a pleiotropic hormone that coordinates an array of physiological processes, including effects on bone, muscle, and fat, ultimately resulting in growth. Metabolically, GH promotes anabolic action in most tissues except adipose, where its catabolic action causes the breakdown of stored triglycerides into free fatty acids (FFA). GH antagonizes insulin action via various molecular pathways. Chronic GH secretion suppresses the anti-lipolytic action of insulin and increases FFA flux into the systemic circulation; thus, promoting lipotoxicity, which causes pathophysiological problems, including insulin resistance. In this review, we will provide an update on GH-stimulated adipose lipolysis and its consequences on insulin signaling in liver, skeletal muscle, and adipose tissue. Furthermore, we will discuss the mechanisms that contribute to the diabetogenic action of GH.

Keywords: CIDEC; FSP27; Fat metabolism; Insulin resistance; Lipolysis; Type 2 diabetes.

Figure 1.. Intracellular model of GH signaling under normal and pathological conditions in Human adipocytes:

Upon stimulation by GH binding, GHR activates Jak2. Activated Jak2 phosphorylates GHR on tyrosine residues which in turn recruit members of the STAT family of transcription factors. Additionally, Src kinase and Shc adaptor proteins are also recruited to the GHR to activate a series of signaling pathways. STATs homodimerize or heterodimerize and translocate to the nucleus to regulate an array of genes under physiological conditions. Coordinated action of STATs and other signaling pathways leads to a balanced state of physiological lipolysis to provide energy for growth, development and metabolism under normal and fasting/starvation conditions. However, chronic levels of elevated GH (as seen in patients with acromegaly) leads to activation of the Ras-Raf-MEK-ERK pathway which dominates other signaling pathways. As a result, phopshorylated ERK translocates to nucleus and phosphorylates PPARγ. Phopshorylated PPARγ is targeted for degradation leading to downregulation of anti-lipolytic genes such as FSP27 and G0S2. Sustained levels of systemic FFAs as a result of deregulated lipolysis cause lipotoxicity and pave the way for the development of insulin resistance, diabetes and related metabolic diseases.

Figure 2.. Synergistic and antagonistic effects of growth hormone and insulin signaling.

Acute GH and insulin exposure act synergistically (as shown in green) to promote normal growth, metabolism, differentiation, and development. However, chronic GH exposure antagonizes insulin action and vice-versa (shown by red arrows) to promote insulin resistance in multiple organs (Liver, skeletal muscle, and adipose tissue) via multiple mechanisms. Dysregulated GH and insulin action, under pathological conditions alter gene/protein expression and their enzymatic activity in insulin sensitive organs to promote insulin resistance that leads to the development of Type 2 diabetes and related metabolic diseases.