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

Abstract

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.

Nesfatin-1 Acts Centrally to Induce Sympathetic Activation of Brown Adipose Tissue and Non-Shivering Thermogenesis

“…We have recently reported a non-significant increase in UCP1 mRNA expression in the iBAT of rats 4 h following i.c.v. administration of nesfatin-1, without changes in protein levels despite a significant increase in iBAT temperature [9]. These observations, together with the present data, suggest that nesfatin-1, when given acutely, may affect responsiveness to UCP1 rather than its production.…”

“…Recently, nesfatin-1 has been reported to increase energy expenditure via CNS pathways. By means of direct calorimetry, we could previously show that the central injection of nesfatin-1 increases energy expenditure to the same extent as leptin [6], and that this effect employs the melanocortin system [9].…”

“…BAT-induced thermogenesis has emerged as a putative targeted response of nesfatin-1, as its central administration has recently been observed to enhance interscapular BAT (iBAT) temperature and up-regulate thermoregulatory genes [9].…”

Endogenous NUCB2/Nesfatin-1 Regulates Energy Homeostasis Under Physiological Conditions in Male Rats

“…To date, information on downstream effector systems of NUCB2/ nesfatin-1 with regard to energy homeostasis has only been collected in experiments employing either central nervous or peripheral administration of nesfatin-1 [2,8]. In these experiments, the melanocortin system has been identified as a crucial mediator of nesfatin-1 action [2,11,33]. Furthermore, we have previously observed that NPY mRNA expression in both hypothalamus and NTS is significantly affected by nesfatin-1 administration [8].…”

“…reward-related feeding [7], but also increases energy expenditure and core body temperature [8][9][10] by recruiting the melanocortin system [11]. In particular, we identified the interscapular brown adipose tissue (iBAT) as major source of heat production [10,11].…”