Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

Corbit, Kevin C.; Wilson, Camella G.; Lowe, Dylan A; Tran, Jennifer L.; Vera, Nicholas B.; Clasquin, Michelle; Mattis, Aras N.; Weiss, Ethan J.

doi:10.1172/jci.insight.131310

Cited by 5 publications

(3 citation statements)

References 62 publications

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“…Excess adiposity in GH-deficient patients can be improved by exogenous GH administration ( 43 ), an effect primarily attributed to GH’s lipolytic action. Male mice with adipocyte-specific deletion of GHR ( 36 ), JAK2 ( 17 – 19 , 37 ) or STAT5 ( 16 ) have increased adiposity also attributed to decreased lipolytic rates, and impaired lipolysis in STAT5 AKO mice has been attributed to decreased ATGL and CGI-58 levels in subcutaneous fat ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, STAT5 proteins regulate adipocyte development [reviewed in ( 14 )], fat mass ( 10 ), and lipid metabolism ( 13 ), through mechanisms that remain enigmatic. JAK2-STAT5 signaling in various tissues contributes to obesity and T2DM ( 15 ), and disruption of the adipocyte JAK2-STAT5 pathway ( 16 ) improves systemic metabolism and liver function ( 17 – 19 ).…”

Section: Introductionmentioning

confidence: 99%

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Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

et al. 2022

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STATs (Signal Transducers and Activators of Transcription) 5A and 5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH) and prolactin in fat cells. Previous studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. Male and female mice harboring adipocyte-specific deletion of both STAT5 genes (STAT5AKO) exhibit increased subcutaneous or inguinal adipose tissue mass, but no changes in visceral or gonadal fat mass. Both depots display substantial increases in adipocyte size with no changes in lipolysis in adipose tissue explants. RNA sequencing analysis of subcutaneous adipose tissue and indirect calorimetry experiments reveal sex-dependent differences in adipose gene expression and whole-body energy expenditure, respectively, resulting from the loss of adipocyte STAT5.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

et al. 2022

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“…However, the extent to which steatosis vs loss of other actions of GHR-signaling contributes to liver injury remains to be determined. It has been shown that the steatosis and associated liver injury and tumor formation are not evident with congenital loss of both liver and adipose JAK2, suggesting GH-mediated metabolic dysfunction of adipose tissue contributes to liver injury in this model (Corbit et al 2019). However, it is becoming evident that hepatic DNL is a major driver of steatosis in mice and humans (Lambert et al 2014, Smith et al 2020) and suppression of DNL improves NASH in a murine diet-induced NASH model (Gapp et al 2020).…”

Section: Discussionmentioning

confidence: 70%

GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

Sarmento‐Cabral

Río-Moreno

Vázquez‐Borrego

et al. 2021

Journal of Endocrinology

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A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function versus indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.

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Sex Differences in Immunometabolism: An Unexplored Area

Mishra¹,

Bassi²,

Xu³

2020

Methods in Molecular Biology

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Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

Cited by 5 publications

References 62 publications

Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

Loss of Adipocyte STAT5 Confers Increased Depot-Specific Adiposity in Male and Female Mice That Is Not Associated With Altered Adipose Tissue Lipolysis

GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner

Sex Differences in Immunometabolism: An Unexplored Area

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