Adipocyte JAK2 mediates aging-associated metabolic liver disease and progression to hepatocellular carcinoma

Abstract

Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyte Jak2 (JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyte Jak2 (JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here suggests a attention be paid towards inhibition of adipocyte GH signaling as a therapeutic target of metabolic liver disease.

Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways

“…We also observe that the increased adiposity of STAT5 AKO mice is not associated with changes in adipose tissue lipolysis. Our data, and studies from other groups (Corbit et al, 2017a(Corbit et al, , 2018(Corbit et al, , 2019, strongly indicate that the mechanism(s) by which the adipocyte JAK2-STAT5 pathway contributes to systemic metabolism are more complex than originally thought. Overall, our studies show that congenital loss of STAT5 in mature adipocytes results in a depot-specific increase in fat mass as well as sex-dependent differences in adipocyte gene expression and whole-body energy expenditure.…”

“…The ability of GH to reduce adipose tissue mass had been primarily attributed to its lipolytic effects. Male mice that lack growth hormone receptor (GHR) (List et al, 2013), JAK2 (Corbit et al, 2017b(Corbit et al, , 2018(Corbit et al, , 2019Nordstrom et al, 2013) or STAT5 (Kaltenecker et al, 2017) specifically in adipocytes have been previously studied. Each of these mouse models have increased adiposity that is attributed to decreased lipolytic rates.…”

“…There are a variety of factors that could account for the difference in phenotypic observations ranging from the genetic drift in mouse strains, animal housing conditions, as well as potential contributions of gut microbiota. Also, our fasting conditions are limited to 4 hours or overnight for some studies, while the observations of increased lipolytic products in serum of adipocyte GHR, JAK2, or STAT5 KOs occur after prolonged fasts ranging up to 48 hours (Corbit et al, 2017b(Corbit et al, , 2018(Corbit et al, , 2019Kaltenecker et al, 2017;List et al, 2013;Nordstrom et al, 2013). It should also be noted that mice lacking the lipolytic mediator, ATGL, specifically in adipocytes have a very different phenotype than mice lacking STAT5 in adipocytes.…”

“…It is largely accepted that GH promotes fat loss via lipolysis and animal models with diminished adipose tissue GH signaling have altered lipolytic responses (Corbit et al, 2017b(Corbit et al, , 2018(Corbit et al, , 2019Kaltenecker et al, 2017;List et al, 2013;Nordstrom et al, 2013). We examined gene and protein expression of several known lipolytic mediators including adipose triglyceride lipase (ATGL), CGI-58 (comparative gene identification-58), and 3 adrenergic receptor (ADRB3).…”

“…The JAK2-STAT5 signaling pathway contributes to obesity pathogenesis and T2DM by impacting a variety of different tissues (Gurzov et al, 2016). Moreover, there is compelling data to show disruption of the JAK2-STAT5 pathway in adipocytes (Kaltenecker et al, 2017) can improve both systemic metabolic functions and liver function (Corbit et al, 2017a(Corbit et al, , 2018(Corbit et al, , 2019.…”