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

Abstract

Nesfatin-1 has originally been established as a bioactive peptide interacting with key hypothalamic nuclei and neural circuitries in control of feeding behavior, while its effect on energy expenditure has only recently been investigated. Hence, the aim of this study was to examine whether centrally acting nesfatin-1 can induce β3-adrenergic stimulation, which is a prerequisite for the activation of thermogenic genes and heat release from interscapular brown adipose tissue, key physiological features that underlie increased energy expenditure. This question was addressed in non-fasted mice stereotactically cannulated to receive nesfatin-1 intracerebroventricularly together with peripheral injection of the β3-adrenoceptor antagonist SR 59230 A, to assess whole-body energy metabolism. Using a minimally invasive thermography technique, we now demonstrate that the thermogenic effect of an anorectic nesfatin-1 dose critically depends on β3 adrenergic stimulation, as the co-administration with SR 59230 A completely abolished heat production from interscapular brown adipose tissue and rise in ocular surface temperature, thus preventing body weight loss. Moreover, through indirect calorimetry it could be shown that the anorectic concentration of nesfatin-1 augments overall caloric expenditure. Plausibly, central administration of nesfatin-1 also enhanced the expression of DIO2 and CIDEA mRNA in brown adipose tissue critically involved in the regulation of thermogenesis.

Nesfatin-1 decreases the motivational and rewarding value of food

“…The anorexigenic properties of nesfatin-1 were reported for the first time by Oh-I and collaborators [ 2 ]. This seminal finding was confirmed and further extended by other research groups [ 3 – 5 ] and by us [ 6 , 7 ]. In addition, nesfatin-1 administration into the central nervous system (CNS) was also shown to increase body core temperature [ 8 ] and energy expenditure [ 6 , 7 , 9 ], thereby indicating its major role in the central regulation of energy homeostasis.…”

“…This seminal finding was confirmed and further extended by other research groups [ 3 – 5 ] and by us [ 6 , 7 ]. In addition, nesfatin-1 administration into the central nervous system (CNS) was also shown to increase body core temperature [ 8 ] and energy expenditure [ 6 , 7 , 9 ], thereby indicating its major role in the central regulation of energy homeostasis. In fact, NUCB2 and/or nesfatin-1 (here named NUCB2/nesfatin-1 as common antibodies do not distinguish between NUCB2 and nesfatin-1) is highly expressed in homeostatic centers such as the hypothalamus and brainstem [ 2 , 10 – 13 ].…”

Knockdown of Endogenous Nucb2/Nesfatin-1 in the PVN Leads to Obese-Like Phenotype and Abolishes the Metformin- and Stress-Induced Thermogenic Response in Rats

“…We previously showed that nesfatin-1 injected i.c.v. promotes thermogenesis by increasing both iBAT and tail temperature (indices of heat production and dissipation, respectively) 5 39 . In the present study, thermal imaging revealed that iBAT and tail temperature in Nucb2/nesfatin-1 knockdown animals did not differ from controls in baseline condition and thus did not account for the difference in energy expenditure.…”

Nesfatin-1 Receptor: Distribution, Signaling and Increasing Evidence for a G Protein-Coupled Receptor – A Systematic Review

“…It was demonstrated that the thermogenetic effect of nesfatin-1 mainly depends on b3-adrenergic stimulation. In addition, levels of Dio2 and cell death inducing DFFA like effector A (CIDEA) mRNA were increased in brown adipose tissue after nesfatin-1 administration, which is plausible as both are involved in regulating the thermogenic program (46). Since the direct effects of peripherally injected nesfatin-1 on vascular smooth muscle were attenuated by pretreatment with propranolol, an involvement of the b-adrenergic system can also be suspected here (57).…”