Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH

Sarah M. Nordstrom, Jennifer L. Tran, Brandon C. Sos, Kay Uwe Wagner, Ethan J. Weiss

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic expression of the metabolic syndrome, and its prevalence is increasing. The factors that influence the development of fatty liver and its progression to steatohepatitis and cirrhosis are not well understood. The pleiotropic hormone, GH, has been associated with an increased risk of NAFLD in humans and mice. GH is known to have diverse effects on lipid metabolism including decreasing body fat in vivo, presumably through stimulation of lipolysis via an undefined mechanism. Previously we described mice with hepatocyte-specific deletion of the GH signaling mediator, Janus kinase 2 (JAK2L). JAK2L animals have elevated serum GH, reduced body fat, high liver triglyceride content, and increased serum markers of hepatocyte injury (alanine transaminase and aspartate transaminase). We aimed to determine whether the elevation of GH in JAK2L mice contributed to fatty liver by promoting lipolysis directly in adipocytes. We generated mice with adipocyte-specific disruption of JAK2 (JAK2A) and found that GH resistance in adipocytes reduced lipolysis and increased body fat. JAK2A mice were then crossed to JAK2L mice, and the resultant JAK2L/A animals had increased body fat and decreased lipolysis, despite elevated circulating GH. Furthermore, the increased triglyceride content, serum alanine transaminase, and serum aspartate transaminase observed in JAK2L mice were nearly normalized with the additional disruption of JAK2 in adipocytes (JAK2L/A mice). Our results offer novel mechanistic insights into the long-recognized effects of GH on lipid flux and suggest that GH signaling may play an important regulatory role in the development of NAFLD.

Original languageEnglish (US)
Pages (from-to)1333-1342
Number of pages10
JournalMolecular Endocrinology
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2013

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Lipolysis
Fatty Liver
Adipocytes
Adipose Tissue
Aspartate Aminotransferases
Alanine Transaminase
Hepatocytes
Triglycerides
Serum
Janus Kinase 2
Liver
Lipid Metabolism
Fibrosis
Biomarkers
Hormones
Lipids
Wounds and Injuries

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH. / Nordstrom, Sarah M.; Tran, Jennifer L.; Sos, Brandon C.; Wagner, Kay Uwe; Weiss, Ethan J.

In: Molecular Endocrinology, Vol. 27, No. 8, 01.08.2013, p. 1333-1342.

Research output: Contribution to journalArticle

Nordstrom, Sarah M. ; Tran, Jennifer L. ; Sos, Brandon C. ; Wagner, Kay Uwe ; Weiss, Ethan J. / Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 8. pp. 1333-1342.
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