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Diabetes. 2018 Feb;67(2):208-221. doi: 10.2337/db17-0524. Epub 2017 Dec 4.

Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling.

Author information

1
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA.
2
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT.
3
Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.
4
Cardiovascular and Metabolic Diseases, Pfizer, Cambridge, MA.
5
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.
6
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT.
7
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA ethan.weiss@ucsf.edu.

Abstract

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism.

PMID:
29203511
PMCID:
PMC5780061
DOI:
10.2337/db17-0524
[Indexed for MEDLINE]
Free PMC Article

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