Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity

Mol Metab. 2018 May:11:33-46. doi: 10.1016/j.molmet.2018.03.008. Epub 2018 Mar 21.

Abstract

Objective: Glucagon-like peptide-1 (GLP-1) neurons in the hindbrain densely innervate the dorsomedial hypothalamus (DMH), a nucleus strongly implicated in body weight regulation and the sympathetic control of brown adipose tissue (BAT) thermogenesis. Therefore, DMH GLP-1 receptors (GLP-1R) are well placed to regulate energy balance by controlling sympathetic outflow and BAT function.

Methods: We investigate this possibility in adult male rats by using direct administration of GLP-1 (0.5 ug) into the DMH, knocking down DMH GLP-1R mRNA with viral-mediated RNA interference, and by examining the neurochemical phenotype of GLP-1R expressing cells in the DMH using in situ hybridization.

Results: GLP-1 administered into the DMH increased BAT thermogenesis and hepatic triglyceride (TG) mobilization. On the other hand, Glp1r knockdown (KD) in the DMH increased body weight gain and adiposity, with a concomitant reduction in energy expenditure (EE), BAT temperature, and uncoupling protein 1 (UCP1) expression. Moreover, DMH Glp1r KD induced hepatic steatosis, increased plasma TG, and elevated liver specific de-novo lipogenesis, effects that collectively contributed to insulin resistance. Interestingly, DMH Glp1r KD increased neuropeptide Y (NPY) mRNA expression in the DMH. GLP-1R mRNA in the DMH, however, was found in GABAergic not NPY neurons, consistent with a GLP-1R-dependent inhibition of NPY neurons that is mediated by local GABAergic neurons. Finally, DMH Glp1r KD attenuated the anorexigenic effects of the GLP-1R agonist exendin-4, highlighting an important role of DMH GLP-1R signaling in GLP-1-based therapies.

Conclusions: Collectively, our data show that DMH GLP-1R signaling plays a key role for BAT thermogenesis and adiposity.

Keywords: Adipose tissue; Hypothalamus; Neuropeptide; Obesity; Sympathetic nerve.

Publication types

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

MeSH terms

  • Adipose Tissue, Brown / metabolism*
  • Adiposity*
  • Animals
  • Exenatide / metabolism
  • GABAergic Neurons / metabolism
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Hypothalamus / metabolism*
  • Insulin Resistance
  • Lipogenesis
  • Male
  • Neuropeptide Y / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Thermogenesis*
  • Uncoupling Protein 1 / metabolism

Substances

  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Neuropeptide Y
  • Ucp1 protein, rat
  • Uncoupling Protein 1
  • Glucagon-Like Peptide 1
  • Exenatide