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• W2528281680 abstract "ABSTRACT Growth Hormone (GH) is a master regulator of metabolic homeostasis and longevity. Whole body GH insensitivity (GHI) augments insulin sensitivity, age-related disease resistance, adiposity, and occurrence of NAFLD. Conversely, acromegalic patients are prone to diabetes and increased mortality due to constitutive high levels of circulating GH. However, which tissues control the various metabolic aspects of GH physiology are unknown. Therefore, we determined the role of GH in age-related metabolic dysfunction by inducing hepatocyte- (JAK2L) or adipocyte-specific (JAK2A) GHI individually or combinatorially (JAK2LA) via deletion of Jak2 , an obligate transducer of GH signaling. Aged JAK2L mice were insulin resistant but lean and had significant NASH, hepatic inflammation, and fibrosis. In contrast, JAK2A animals had increased adiposity and were completely resistant to age-associated hepatic steatosis, NASH, and insulin resistance. Interestingly, while JAK2LA mice retained enhanced whole-body insulin sensitivity, they still developed NASH to an almost identical degree as JAK2L mice but with a substantial reduction in the degree of microvesicular steatosis. Collectively, loss of adipocyte Jak2 conferred whole body insulin sensitivity even in the face of obesity and NASH. Deletion of hepatocyte Jak2 promoted NASH in aged mice without any dietary or drugs perturbations. The effect appears to be liver autonomous and cannot be overcome by the insulin sensitizing effect of adipocyte Jak2 deletion. Here, we describe the first model of spontaneous NASH that is coupled to augmented insulin sensitivity. Further, there was an inverse correlation between insulin sensitivity and the degree of microvesicular steatosis. Therefore, GH signaling independently mediates insulin/glucose and lipid homeostasis and directly regulates the development of NASH in aged mice. Financial Support: This study was supported by National Institutes of Health (NIH) Grants 1R01DK091276 (to E.J.W.). We also acknowledge the support of the University of California, San Francisco (UCSF) Cardiovascular Research Institute, the UCSF Diabetes Center (P30 DK063720), the UCSF Liver Center (P30 DK026743, and the James Peter Read Foundation. Abbreviations NASH non-alcoholic steato-hepatitis NAFLD non-alcoholic fatty liver disease GH growth hormone JAK2 Janus kinase 2 CON CON mice JAK2L hepatocyte-specific deletion of JAK2 JAK2A adipocyte-specific deletion of JAK2 JAK2LA hepatocyte and adipocyte JAK2 knockout TG triglyceride AST aspartate aminotransferase ALT alanine transaminase Stat5 signal transducer and activator of transcription 5 qRT-PCR quantitative reverse-transcription polymerase chain reaction Mcp1 monocyte chemoattractant protein-1 Cd11b cluster of differentiation molecule 11b F4/80 EGF-like module-containing mucin-like hormone receptor-like 1 FcgR1 high affinity immunoglobulin gamma Fc receptor I L-Fabp liver fatty acid binding protein PPARγ peroxisome proliferator-activated receptor gamma FATP fatty acid transport protein CD36/FAT Fatty Acid Translocase ITT insulin tolerance test. Lpl lipoprotein lipase IL- interleukin- FcgR1 Fc receptor IgG Tnfα tumor necrosis factor alpha Tgfβ1 transforming growth factor beta 1 αSMA, alpha 2 smooth muscle actin IGF-1 insulin-like growth factor 1." @default.
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• W2528281680 date "2016-10-04" @default.
• W2528281680 modified "2023-09-23" @default.
• W2528281680 title "Disruption of Hepatocyte Jak2 leads to Spontaneous NASH in Aged Mice and Uncouples Metabolic Liver Disease from Insulin Resistance" @default.
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• W2528281680 doi "https://doi.org/10.1101/079236" @default.
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