TNF-related apoptosis-inducing ligand promotes human preadipocyte proliferation via ERK1/2 activation

FASEB J. 2015 Jul;29(7):3065-75. doi: 10.1096/fj.14-267278. Epub 2015 Apr 9.

Abstract

Upon obesity, adipose tissue is excessively expanded and characterized by pathologic processes like hypoxia, fibrosis, and inflammation. Death ligands belonging to the TNF superfamily such as TNF-α are important contributors to these derangements and exert a pronounced influence on the metabolic and cellular homeostasis of adipose tissue. Here, we sought to identify the effect of the death ligand TNF-related apoptosis-inducing ligand (TRAIL) on the adipose tissue precursor cell pool and therefore investigated its influence on preadipocyte proliferation. Treatment of human preadipocytes with TRAIL resulted in a time- and dose-dependent increase in proliferation (EC50 3.4 ng/ml) comparable to IGF-1. Although no apoptosis was observed, TRAIL triggered a rapid cleavage of caspase-8 and -3. Neither inhibition of caspase activity by zVAD.fmk (20 µM) nor ablation of caspase-8 expression by lentivirus-delivered small hairpin RNA (shRNA) abolished the proliferative response. TRAIL triggered a delayed and sustained activation of ERK1/2, leaving Akt, p38, JNK, and NF-κB unaffected. Importantly, inhibition of ERK1/2 activation by PD0325901 (300 nM) or AZD6244 (5 or 10 µM) completely abolished the proliferative response. We thus reveal a hitherto unknown function of TRAIL in regulating adipose tissue homeostasis by promoting the proliferation of tissue-resident precursor cells.

Keywords: adipocyte progenitor; adipose tissue homeostasis; death ligand; noncanonical signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, White / cytology*
  • Adipocytes, White / drug effects
  • Adipocytes, White / metabolism*
  • Adult
  • Adult Stem Cells / cytology*
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / metabolism*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Benzamides / pharmacology
  • Benzimidazoles / pharmacology
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Diphenylamine / analogs & derivatives
  • Diphenylamine / pharmacology
  • Female
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Gigantism / metabolism
  • Gigantism / pathology
  • Heart Defects, Congenital / metabolism
  • Heart Defects, Congenital / pathology
  • Humans
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • MAP Kinase Signaling System* / drug effects
  • NF-kappa B / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology

Substances

  • AZD 6244
  • Benzamides
  • Benzimidazoles
  • NF-kappa B
  • PD 0325901
  • Protein Kinase Inhibitors
  • RNA, recombinant
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • RNA
  • Diphenylamine
  • Proto-Oncogene Proteins c-akt
  • CASP8 protein, human
  • Caspase 8

Supplementary concepts

  • Simpson-Golabi-Behmel syndrome