aP2-Cre Mediated Ablation of GHS-R Attenuates Adiposity and Improves Insulin Sensitivity during Aging

Int J Mol Sci. 2018 Oct 1;19(10):3002. doi: 10.3390/ijms19103002.

Abstract

Ghrelin via its receptor, the growth hormone secretagogue receptor (GHS-R), increases food intake and adiposity. The tissue-specific functions of GHS-R in peripheral tissues are mostly unknown. We previously reported that while GHS-R expression is very low in white and brown fat of young mice, expression increases during aging. To investigate whether GHS-R has cell-autonomous effects in adipose tissues, we generated aP2-Cre-mediated GHS-R knockdown mice (aP2-Cre/Ghsrf/f). We studied young (5⁻6 months) and old (15⁻17 months) aP2-Cre/Ghsrf/f mice and their age-matched controls. Interestingly, young aP2-Cre/Ghsrf/f mice had normal body weight but reduced fat; old mice showed pronounced reductions of both body weight and body fat. Calorimetry analysis revealed that aP2-Cre/Ghsrf/f mice had normal food intake and locomotor activity at both young and old age; but intriguingly, while energy expenditure was normal at young age, it was significantly increased at old age. Both young and old aP2-Cre/Ghsrf/f mice exhibited improved insulin sensitivity and glucose tolerance. Importantly, old aP2-Cre/Ghsrf/f mice maintained higher core body temperature at 4 °C, and showed higher expression of the thermogenic uncoupling protein 1 (UCP1) gene. The ex vivo studies further demonstrated that GHS-R deficient white adipocytes from old mice exhibit increased glucose uptake and lipolysis, promoting lipid mobilization. Despite the fact that the in vivo phenotypes of aP2-Cre/Ghsrf/f mice may not be exclusively determined by GHS-R knockdown in adipose tissues, our data support that GHS-R has cell-autonomous effects in adipocytes. The anabolic effect of GHS-R in adipocytes is more pronounced in aging, which likely contributes to age-associated obesity and insulin resistance.

Keywords: GHS-R; UCP1; adipose tissues; ghrelin; thermogenesis; tissue-specific knockdown mice.

MeSH terms

  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Adiposity* / drug effects
  • Aging / metabolism*
  • Animals
  • Carbohydrates / chemistry
  • Eating / drug effects
  • Energy Metabolism
  • Fatty Acid-Binding Proteins / genetics*
  • Gene Deletion*
  • Gene Knockdown Techniques
  • Ghrelin / pharmacology
  • Glucose Tolerance Test
  • Growth Hormone / metabolism
  • Insulin Resistance*
  • Integrases / metabolism*
  • Lipolysis / drug effects
  • Metabolomics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proteins / metabolism*
  • Receptors, Ghrelin / metabolism*
  • Thermogenesis / drug effects

Substances

  • Carbohydrates
  • Fabp4 protein, mouse
  • Fatty Acid-Binding Proteins
  • Ghrelin
  • Proteins
  • Receptors, Ghrelin
  • Growth Hormone
  • Cre recombinase
  • Integrases