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Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance
Kevin C. Corbit, … , Michael J. Jurczak, Ethan J. Weiss
Kevin C. Corbit, … , Michael J. Jurczak, Ethan J. Weiss
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e91001. https://doi.org/10.1172/jci.insight.91001.
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Research Article Endocrinology Metabolism

Adipocyte JAK2 mediates growth hormone–induced hepatic insulin resistance

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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 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 extrahepatic, adipose tissue–dependent mechanism.

Authors

Kevin C. Corbit, João Paulo G. Camporez, Jennifer L. Tran, Camella G. Wilson, Dylan A. Lowe, Sarah M. Nordstrom, Kirthana Ganeshan, Rachel J. Perry, Gerald I. Shulman, Michael J. Jurczak, Ethan J. Weiss

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Figure 4

Loss of adipocyte Jak2 imparts hepatic and whole-body insulin sensitivity in high-fat diet–fed mice.

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Loss of adipocyte Jak2 imparts hepatic and whole-body insulin sensitivit...
(A) Plasma glucose levels and (B) glucose infusion rate (GIR) during glucose infusion to achieve euglycemia in control (CON, black circles) and JAK2A (white circles) mice. (C) GIR at euglycemia in control and JAK2A mice. (D) Basal and (E) clamped endogenous glucose production (EGP) in control and JAK2A mice. (F) Percentage suppression of EGP following insulin infusion in control and JAK2A mice. (G) Whole-body glucose uptake in control and JAK2A mice. (H) 2-Deoxyglucose (2-DG) uptake in gastrocnemius and (I) epididymal visceral fat in control and JAK2A mice. (J) Basal and (K) clamped plasma fatty acid (FFA) levels in control and JAK2A mice. (L) Percentage suppression of plasma FFA following insulin infusion in control and JAK2A mice. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA. n = 8–11 for both cohorts. Data represent ± SEM.

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