Suppression of GHS-R in AgRP Neurons Mitigates Diet-Induced Obesity by Activating Thermogenesis

Int J Mol Sci. 2017 Apr 14;18(4):832. doi: 10.3390/ijms18040832.


Ghrelin, an orexigenic hormone released primarily from the gut, signals the hypothalamus to stimulate growth hormone release, enhance appetite and promote weight gain. The ghrelin receptor, aka Growth Hormone Secretagogue Receptor (GHS-R), is highly expressed in the brain, with highest expression in Agouti-Related Peptide (AgRP) neurons of the hypothalamus. We recently reported that neuron-specific deletion of GHS-R completely prevents diet-induced obesity (DIO) in mice by activating non-shivering thermogenesis. To further decipher the specific neuronal circuits mediating the metabolic effects of GHS-R, we generated AgRP neuron-specific GHS-R knockout mice (AgRP-Cre;Ghsrf/f). Our data showed that GHS-R in AgRP neurons is required for ghrelin's stimulatory effects on growth hormone secretion, acute food intake and adiposity, but not for long-term total food intake. Importantly, deletion of GHS-R in AgRP neurons attenuated diet-induced obesity (DIO) and enhanced cold-resistance in mice fed high fat diet (HFD). The HFD-fed knockout mice showed increased energy expenditure, and exhibited enhanced thermogenic activation in both brown and subcutaneous fat; this implies that GHS-R suppression in AgRP neurons enhances sympathetic outflow. In summary, our results suggest that AgRP neurons are key site for GHS-R mediated thermogenesis, and demonstrate that GHS-R in AgRP neurons plays crucial roles in governing energy utilization and pathogenesis of DIO.

Keywords: Agouti-related peptide (AgRP); diet-induced obesity (DIO); ghrelin; growth hormone secretagogue receptor (GHS-R); thermogenesis.

MeSH terms

  • Agouti-Related Protein / metabolism*
  • Animals
  • Diet, High-Fat
  • Disease Models, Animal
  • Energy Metabolism
  • Feeding Behavior
  • Gene Deletion
  • Growth Hormone / metabolism
  • Homeostasis
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Neurons / metabolism*
  • Obesity / etiology*
  • Obesity / metabolism*
  • Peptide Fragments / metabolism*
  • Receptors, Ghrelin / genetics*
  • Receptors, Ghrelin / metabolism*
  • Thermogenesis*


  • Agouti-Related Protein
  • Peptide Fragments
  • Receptors, Ghrelin
  • agouti-related peptide, (Yc(CRFFNAFC)Y)
  • Growth Hormone