The thermogenic effect of nesfatin-1 requires recruitment of the melanocortin system

J Endocrinol. 2017 Nov;235(2):111-122. doi: 10.1530/JOE-17-0151. Epub 2017 Aug 29.


Nesfatin-1 is a bioactive polypeptide expressed both in the brain and peripheral tissues and involved in the control of energy balance by reducing food intake. Central administration of nesfatin-1 significantly increases energy expenditure, as demonstrated by a higher dry heat loss; yet, the mechanisms underlying the thermogenic effect of central nesfatin-1 remain unknown. Therefore, in this study, we sought to investigate whether the increase in energy expenditure induced by nesfatin-1 is mediated by the central melanocortin pathway, which was previously reported to mediate central nesfatin-1´s effects on feeding and numerous other physiological functions. With the application of direct calorimetry, we found that intracerebroventricular nesfatin-1 (25 pmol) treatment increased dry heat loss and that this effect was fully blocked by simultaneous administration of an equimolar dose of the melanocortin 3/4 receptor antagonist, SHU9119. Interestingly, the nesfatin-1-induced increase in dry heat loss was positively correlated with body weight loss. In addition, as assessed with thermal imaging, intracerebroventricular nesfatin-1 (100 pmol) increased interscapular brown adipose tissue (iBAT) as well as tail temperature, suggesting increased heat production in the iBAT and heat dissipation over the tail surface. Finally, nesfatin-1 upregulated pro-opiomelanocortin and melanocortin 3 receptor mRNA expression in the hypothalamus, accompanied by a significant increase in iodothyronine deiodinase 2 and by a nonsignificant increase in uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha mRNA in the iBAT. Overall, we clearly demonstrate that nesfatin-1 requires the activation of the central melanocortin system to increase iBAT thermogenesis and, in turn, overall energy expenditure.

Keywords: POMC; brown adipose tissue; energy expenditure; nesfatin-1; thermogenesis.

MeSH terms

  • Animals
  • Biomarkers
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Ear
  • Hypothalamus / metabolism
  • Male
  • Melanocortins / metabolism*
  • Melanocyte-Stimulating Hormones / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nucleobindins
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Melanocortin / antagonists & inhibitors
  • Receptors, Melanocortin / genetics
  • Receptors, Melanocortin / metabolism
  • Tail
  • Thermogenesis / physiology*
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism


  • Biomarkers
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Melanocortins
  • Nerve Tissue Proteins
  • Nucb1 protein, rat
  • Nucleobindins
  • RNA, Messenger
  • Receptors, Melanocortin
  • Ucp1 protein, rat
  • Uncoupling Protein 1
  • SHU 9119
  • Melanocyte-Stimulating Hormones