Heme oxygenase (HO-1) rescue of adipocyte dysfunction in ho-2 deficient mice via recruitment of epoxyeicosatrienoic acids (EETs) and adiponectin

Angela P H Burgess, Luca Vanella, Lars Bellner, Katherine Gotlinger, John R. Falck, Nader G. Abraham, Michal L. Schwartzman, Attallah Kappas

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Background/Aims: HO-1 and EETs are functionally linked and their interactions influence body weight, insulin sensitivity, and serum levels of inflammatory cytokines in metabolic syndrome phenotype of HO-2 null mice. The HO-2 isozyme is essential for regulating physiological levels of ROS. Recent studies have suggested a potential role of EET in modifying adipocyte differentiation through up-regulation of HO-1-adiponectin-AkT signaling in human mesenchymal stem cells (MSCs). Our aim was to examine the consequences of HO deficiency on MSC-derived adipogenesis in vitro using MSC derived from HO-2 null and WT mice in vivo. Methods: Four-month-old HO-2 null (HO-2 -/-) and B6/129SF2/J (WT) mice were divided into three groups (four mice/group): WT, HO-2 -/-, and HO-2 -/- +CoPP. Adipogenesis was performed on purified MSC-derived adipocytes cultured in adipogenic differentiation media and an EET-agonist was added every 3 days. Results: HO-2 depletion of MSC adipocytes resulted in increased adipogenesis (p<0.01) and increased levels of inflammatory cytokines including (TNF)-alpha (p<0.05), (MCP)-1 (p<0.05), and (IL-1)-beta (p<0.05). These results were accompanied by decreases in HO-1 (p<0.05) and subsequently EET and HO activity (p<0.05). Up-regulation of HO-1 resulted in decreased MSC-derived adipocyte differentiation, decreased production of TNF-alpha and MCP-1 and increased levels of adiponectin (p<0.05). Cyp2J5 (p<0.05), HO-1 (p<0.05), and adiponectin mRNA levels (p<0.05) were also decreased in visceral adipose tissue isolated from HO-2 null compared to WT mice. EET agonist stimulation of MSC adipocytes derived from HO-2 null mice yielded similar results. Conclusion: Increased levels of EET and HO-1 are essential for protection against the adverse effects of adipocyte hypertrophy and the ensuing metabolic syndrome. These results offer a portal into therapeutic approaches for the prevention of the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)99-110
Number of pages12
JournalCellular Physiology and Biochemistry
Volume29
Issue number1-2
DOIs
Publication statusPublished - 2012

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Keywords

  • Antioxidants
  • Bilirubin
  • Carbon monoxide
  • Cardiovascular
  • Diabetes
  • HO
  • Stress response genes

ASJC Scopus subject areas

  • Physiology

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