Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance

Abstract

For nearly 100 years, Growth Hormone (GH) has been known to regulate insulin sensitivity and risk of diabetes. However, the tissue governing the effects of GH signaling on insulin and glucose homeostasis remains unknown. Excess GH reduces fat mass and insulin sensitivity. Conversely, GH insensitivity (GHI) is associated with increased adiposity, augmented insulin sensitivity, and protection from diabetes.Here we induce adipocyte-specific GHI through conditional deletion of Jak2 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte Jak2 augmented hepatic insulin sensitivity and conferred resistance to diet-induced metabolic stress without overt changes in circulating fatty acids. While GH injections induced hepatic insulin resistance in control mice, the diabetogenic action was absent in JAK2A mice. Collectively, our results show that adipose tissue governs the effects of GH on insulin and glucose homeostasis. Further, we show that JAK2 mediates liver insulin sensitivity via an extra-hepatic, adipose tissue-dependent mechanism.

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

“…To directly address this, Cordoba-Chacon et al (47) used adipose explant cultures to demonstrate that aHepGHRkd had normal basal and stimulated rates of lipolysis. This is also consistent with our previously published results showing that GH does not affect basal lipolysis but instead specifically interferes with the ability of insulin to suppress lipolysis (19). Thus, without directly attending to high circulating GH levels present in aHepGHRkd mice via concomitant loss of adipocyte Ghr or global Gh disruption, it is premature to conclude that fatty liver and NASH resulting from loss of hepatocyte Ghr occurs via liver-autonomous means.…”

“…Females are relatively protected from metabolic dysregulation in both humans and mice, and this has been attributed to, among other sex-based differences, a preferential partitioning of FA toward ketogenesis over VLDL TAG production (60). Our studies here were a follow-up to previous work using hyperinsulinemic-euglycemic clamps (19,20), where the high degree of variability between female animals when using this technique presented a resource-based limitation for us. Therefore, females were not included in the current aging study because we have yet to definitely determine the state of insulin sensitivity in either JAK2L or JAK2LA female mice.…”

“…Thus, elevated GH activity on adipose tissue may be a commonality among GH-resistant and IR states, including starvation, LD, and NAFLD/NASH. GH is a major regulator of glucose and lipid metabolism (19,20). Congenital loss of global GH signaling increases insulin sensitivity and adiposity and may decrease the incidence of diabetes and cancer (21,22).…”

“…Congenital loss of global GH signaling increases insulin sensitivity and adiposity and may decrease the incidence of diabetes and cancer (21,22). Conversely, exposure to GH acutely (19) or chronically, in the setting of acromegaly, induces IR (23). Somewhat paradoxically, adult-onset GH deficiency also predisposes to fatty liver and NASH (24), possibly by a different mechanism via direct effects on hepatic DNL (25).…”

Loss of growth hormone–mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity

“…FGF1 has powerful insulin synergistic actions and is synthesized and secreted from adipose tissues (50, 73). Importantly, a recent study in adipose tissue‐specific Jak2 knockout mice has revealed a marked increase in hepatic insulin sensitivity and postulated that this was a result of altered secretion of an adipose tissue factor (74). It is plausible that this factor is indeed FGF1 and that it acts in an endocrine manner to increase insulin sensitivity in the obese Ghr ‐391 −/− and Ghr −/− mice.…”