Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance

Abstract

For nearly 100 years, growth hormone (GH) has been known to affect 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 (JAK2A), an obligate transducer of GH signaling. Similar to whole-body GHI, JAK2A mice had increased adiposity and extreme insulin sensitivity. Loss of adipocyte 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. Adipocyte GH signaling directly impinged on both adipose and hepatic insulin signal transduction. 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 extrahepatic, adipose tissue-dependent mechanism.

Increased ATP synthesis might counteract hepatic lipid accumulation in acromegaly

“…Circulating FFA originating from adipose tissue as well as directly from nutrition are generally regarded as a major source for ectopic lipid accumulation, and there is evidence that aside from ectopic lipids and adipose tissue, GH-induced lipolysis plays a role in the interorgan transfer of lipids and the induction of IR (32,33). Interestingly, no changes were found in concentrations of FFA species, except (C18:3), which was markedly lower in subjects with ACRO.…”

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

“…Adipose-specific Jak2 KO mice have demonstrated defective lipolysis, increased body weight and adiposity compared to controls, leading to IR (Nordstrom et al, 2013;Shi et al, 2014;Corbit et al, 2017). Similarly, loss of either Stat3 or Stat5 in AT contributes to increased weight gain, adiposity, and impaired lipolysis (Dodington et al, 2018).…”

“…There is a controversy over the effects of adipocyte JAK2/STAT5 on insulin sensitivity. Some studies have shown IR (Shi et al, 2014) while others have demonstrated enhanced whole-body insulin sensitivity in the absence of JAK2 or STAT5 (Nordstrom et al, 2013;Corbit et al, 2017). This inconsistency might be due to a variety of factors including tissue specificity and cell stage-dependent expression of the cre transgene, mouse genetic background, physiologic status, and other environmental factors in which the experiments were performed (Dodington et al, 2018).…”

Insulin: too much of a good thing is bad

“…Permanently elevated insulin concentrations in the blood are often considered as an attempt to overcome insulin resistance. Indeed, induction of insulin resistance by genetic disruption of insulin signaling, as well as by increased growth hormone levels or an inflammatory milieu, causes hyperinsulinemia [68][69][70]. The opposite causality is of more relevance.…”