Ghrelin receptor regulates adipose tissue inflammation in aging

Aging (Albany NY). 2016 Jan;8(1):178-91. doi: 10.18632/aging.100888.


Aging is commonly associated with low-grade adipose inflammation, which is closely linked to insulin resistance. Ghrelin is the only circulating orexigenic hormone which is known to increase obesity and insulin resistance. We previously reported that the expression of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), increases in adipose tissues during aging, and old Ghsr(-/-) mice exhibit a lean and insulin-sensitive phenotype. Macrophages are major mediators of adipose tissue inflammation, which consist of pro-inflammatory M1 and anti-inflammatory M2 subtypes. Here, we show that in aged mice, GHS-R ablation promotes macrophage phenotypical shift toward anti-inflammatory M2. Old Ghsrp(-/-) mice have reduced macrophage infiltration, M1/M2 ratio, and pro-inflammatory cytokine expression in white and brown adipose tissues. We also found that peritoneal macrophages of old Ghsrp(-/-) mice produce higher norepinephrine, which is in line with increased alternatively-activated M2 macrophages. Our data further reveal that GHS-R has cell-autonomous effects in macrophages, and GHS-R antagonist suppresses lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Collectively, our studies demonstrate that ghrelin signaling has an important role in macrophage polarization and adipose tissue inflammation during aging. GHS-R antagonists may serve as a novel and effective therapeutic option for age-associated adipose tissue inflammation and insulin resistance.

Keywords: adipose tissue macrophages (ATMs); ghrelin; growth hormone secretagogue receptor (GHS-R); inflammation; peritoneal macrophages (PM); thermogenesis.

Publication types

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

MeSH terms

  • Age Factors
  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Cell Plasticity
  • Genetic Predisposition to Disease
  • Hormone Antagonists / pharmacology
  • Inflammation Mediators / metabolism
  • Insulin Resistance
  • Intra-Abdominal Fat / drug effects
  • Intra-Abdominal Fat / metabolism*
  • Lipolysis
  • Lipopolysaccharides / pharmacology
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Panniculitis / genetics
  • Panniculitis / metabolism*
  • Panniculitis / prevention & control
  • Phenotype
  • RAW 264.7 Cells
  • Receptors, Ghrelin / antagonists & inhibitors
  • Receptors, Ghrelin / deficiency
  • Receptors, Ghrelin / genetics
  • Receptors, Ghrelin / metabolism*


  • Anti-Inflammatory Agents
  • Ghsr1a protein, mouse
  • Hormone Antagonists
  • Inflammation Mediators
  • Lipopolysaccharides
  • Receptors, Ghrelin