The PVH as a site of CB1-mediated stimulation of thermogenesis by MC4R agonism in male rats

Endocrinology. 2014 Sep;155(9):3448-58. doi: 10.1210/en.2013-2092. Epub 2014 Jun 20.


The present study was designed to investigate the involvement of the cannabinoid receptor 1 (CB1) in the stimulating effects of the melanocortin-4 receptor (MC4R) agonism on whole-body and brown adipose tissue (BAT) thermogenesis. In a first series of experiments, whole-body and BAT thermogenesis were investigated in rats infused in the third ventricle of the brain with the MC4R agonist melanotan II (MTII) and the CB1 agonist δ9-tetrahydrocannabinol (δ(9)-THC) or the CB1 antagonist AM251. Whole-body thermogenesis was measured by indirect calorimetry and BAT thermogenesis assessed from interscapular BAT (iBAT) temperature. δ(9)-THC blunted the effects of MTII on energy expenditure and iBAT temperature, whereas AM251 tended to potentiate the MTII effects. δ(9)-THC also blocked the stimulating effect of MTII on (14)C-bromopalmitate and (3)H-deoxyglucose uptakes in iBAT. Additionally, δ(9)-THC attenuated the stimulating effect of MTII on the expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1α), type II iodothyronine deiodinase (Dio2), carnitine palmitoyltransferase 1B (Cpt1b), and uncoupling protein 1 (Ucp1). In a second series of experiments, we addressed the involvement of the paraventricular hypothalamic nucleus (PVH) in the CB1-mediated effects of MTII on iBAT thermogenesis, which were assessed following the infusion of MTII in the PVH and δ(9)-THC or AM251 in the fourth ventricle of the brain. We demonstrated the ability of δ(9)-THC to blunt MTII-induced iBAT temperature elevation. δ(9)-THC also blocked the PVH effect of MTII on (14)C-bromopalmitate uptake as well as on Pgc1α and Dio2 expression in iBAT. Altogether the results of this study demonstrate the involvement of the PVH in the CB1-mediated stimulating effects of the MC4R agonist MTII on whole-body and BAT thermogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Male
  • Paraventricular Hypothalamic Nucleus / metabolism*
  • Peptides, Cyclic / metabolism*
  • Piperidines
  • Pyrazoles
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / agonists
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / genetics
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Melanocortin, Type 4 / agonists*
  • Receptor, Melanocortin, Type 4 / metabolism
  • Thermogenesis*
  • alpha-MSH / analogs & derivatives*
  • alpha-MSH / metabolism


  • Cnr1 protein, rat
  • Peptides, Cyclic
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Melanocortin, Type 4
  • melanotan-II
  • AM 251
  • alpha-MSH