Growth Hormone Signaling via JAK2 in Adipocytes Regulates Insulin Sensitivity in Mice Independent of Body Composition and Hepatic Lipid Content Through Alteration of Hepatic Insulin Sensitivity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 88-108-GHRH, GH & IGF Biology & Signaling
Basic/Translational
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-93
Sarah Melissa Nordstrom*, Jennifer Lynn Tran, Dongmei Wu and Ethan James Weiss
University of California, San Francisco, San Francisco, CA
Growth hormone (GH) is a known regulator of metabolism; levels of circulating GH are inversely correlated with body fat, ostensibly through its promotion of lipolysis in adipose tissue. GH excess also leads to insulin resistance (IR), while disruption of GH signaling improves insulin sensitivity (IS). The mechanisms by which GH regulates carbohydrate metabolism are unclear. We disrupted GH signaling in hepatocytes by deleting the GH signaling mediator, JAK2 (JAK2L). JAK2L mice have elevated circulating GH and thus, greater lipolysis and reduced body fat. In addition, JAK2L mice have severe fatty liver (FL), hepatic IR, and whole body IR. To determine if the IR of JAK2L mice can be attributed to the accumulation of hepatic lipid, we additionally disrupted JAK2 in adipocytes to decrease GH-stimulated lipolysis (JAK2L/A). JAK2L/A mice had hepatic lipid content and IS that was comparable to CON animals. However, following high fat diet (HFD), JAK2L and JAK2L/A mice had similar hepatic lipid accumulation, but JAK2L/A animals maintained greater IS compared to JAK2L, indicating that the improved IS of JAK2L/A mice is not necessarily related to hepatic lipid content. Furthermore, JAK2L/A mice had higher body fat on both normal chow and HFD relative to matched JAK2L animals, indicating that the improved IS in JAK2L/A was not due a reduction in body fat. To determine if the singular deletion of JAK2 in adipocytes (JAK2A) influences IS, we compared JAK2A to CON animals. Like JAK2L/A, JAK2A mice were obese compared to CON; yet, JAK2A mice had improved IS. Following HFD, both CON and JAK2A mice developed obesity, but JAK2A remained relatively IS. Furthermore, the improved whole body IS was not explained by changes in hepatic lipid content or IS in muscle or fat. Overall, our findings indicate that GH signaling via JAK2 in adipocytes regulates hepatic IS and whole body IS, independent of changes in body fat and hepatic lipid content. We speculate that the effects of GH on IS are mediated by a JAK2-regulated adipokine that alters IS in liver. Further defining the effects of GH on metabolism could lead to novel treatments for IR that are independent of weight loss and fatty liver.

Nothing to Disclose: SMN, JLT, DW, EJW

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