RT Journal Article SR Electronic T1 Adipocyte JAK2 Mediates Growth Hormone-Induced Hepatic Insulin Resistance JF bioRxiv FD Cold Spring Harbor Laboratory SP 076265 DO 10.1101/076265 A1 Kevin C. Corbit A1 João Paulo G. Camporez A1 Jennifer L. Tran A1 Camella G. Wilson A1 Dylan Lowe A1 Sarah Nordstrom A1 Kirthana Ganeshan A1 Rachel J. Perry A1 Gerald I. Shulman A1 Michael J. Jurczak A1 Ethan J. Weiss YR 2016 UL http://biorxiv.org/content/early/2016/12/01/076265.abstract AB For nearly 100 years, Growth Hormone (GH) has been known to impact 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. 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 extra-hepatic, adipose tissue-dependent mechanism.