Heme oxygenase-mediated increases in adiponectin decrease fat content and inflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in Zucker rats and reduce adipogenesis in human mesenchymal stem cells

J Pharmacol Exp Ther. 2008 Jun;325(3):833-40. doi: 10.1124/jpet.107.135285. Epub 2008 Mar 11.

Abstract

Adiponectin, an abundant adipocyte-derived plasma protein that modulates vascular function in type 2 diabetes, has been shown to provide cytoprotection to both pancreatic and vascular systems in diabetes. Therefore, we examined whether up-regulation of heme oxygenase (HO)-1 ameliorates the levels of inflammatory cytokines and influences serum adiponectin in Zucker fat (ZF) rats. ZF rats displayed a decrease in both HO activity and HO-1 and HO-2 protein levels and an increase in tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 compared with Zucker lean (ZL) rats. Treatment of ZF animals with 2 mg/kg cobalt protoporphyrin IX (CoPP) increased protein levels of HO-1 and HO activity, but HO-2 was unaffected. The increase in HO-1 was associated with a decrease in superoxide levels (p < 0.05) and an increase in plasma adiponectin (p < 0.005), compared with untreated ZF rats. CoPP treatment decreased visceral and s.c. fat content, and it reduced weight gain (p < 0.01). In addition, the inflammatory cytokines TNF-alpha and IL-6 were decreased (p < 0.04 and p < 0.008, respectively). Treatment of human bone marrow-derived adipocytes cultured with CoPP resulted in an increase in HO-1 and a decrease in superoxide levels. Up-regulation of HO-1 caused adipose remodeling, smaller adipocytes, and increased adiponectin secretion in the culture medium of human bone marrow-derived adipocytes. In summary, this study demonstrates that the antiobesity effect of HO-1 induction results in an increase in adiponectin secretion, in vivo and in vitro, a decrease in TNF-alpha and IL-6, and a reduction in weight gain. These findings highlight the pivotal role and symbiotic relationship of HO-1 and adiponectin in the modulation of the metabolic syndrome phenotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipogenesis* / drug effects
  • Adiponectin / blood*
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / metabolism
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Interleukin-6 / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Male
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Metalloporphyrins / pharmacology
  • Myocardium / metabolism
  • Obesity / metabolism*
  • Protoporphyrins / pharmacology
  • Rats
  • Rats, Zucker
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Adiponectin
  • Interleukin-6
  • Metalloporphyrins
  • Protoporphyrins
  • Tumor Necrosis Factor-alpha
  • tin mesoporphyrin
  • Superoxides
  • cobaltiprotoporphyrin
  • Heme Oxygenase-1