Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue

Cell Rep. 2017 Jan 3;18(1):225-236. doi: 10.1016/j.celrep.2016.12.028.

Abstract

Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor α (TNF-α)-treated primary white adipocytes. TNF-α-mediated suppression of sGCβ1 is mediated via NF-κB, whereas PKG is repressed by JNK signaling. Additionally, TNF-α-activated JNK signaling suppresses PPARγ and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.

Keywords: PKG; TNF-α; cGMP signaling; metaflammation; obesity; sGC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cyclic GMP / metabolism*
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Down-Regulation / drug effects
  • Female
  • Gonads / metabolism
  • Guanylate Cyclase / metabolism
  • Humans
  • Inflammation / complications
  • Inflammation / metabolism*
  • Inflammation / pathology*
  • Inguinal Canal / physiology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Obese
  • Models, Biological
  • NF-kappa B / metabolism
  • Obesity / complications
  • Obesity / metabolism*
  • Obesity / pathology*
  • Phenotype
  • Signal Transduction* / drug effects
  • Solubility
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Cyclic GMP-Dependent Protein Kinases
  • Guanylate Cyclase
  • Cyclic GMP