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

Cell Physiol Biochem. 2012;29(1-2):99-110. doi: 10.1159/000337591. Epub 2012 Mar 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipogenesis / drug effects
  • Adiponectin / genetics
  • Adiponectin / metabolism*
  • Animals
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Eicosanoids / metabolism*
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase (Decyclizing) / metabolism
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / metabolism*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Mesenchymal Stem Cells / cytology
  • Metalloporphyrins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protoporphyrins / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adiponectin
  • Chemokine CCL2
  • Eicosanoids
  • Interleukin-1beta
  • Metalloporphyrins
  • Protoporphyrins
  • Tumor Necrosis Factor-alpha
  • tin mesoporphyrin
  • cobaltiprotoporphyrin
  • Cytochrome P-450 Enzyme System
  • arachidonate epoxygenase
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • heme oxygenase-2