Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius

Abstract

Neurons in the ventrolateral medulla (VLM) and in the nucleus tractus solitarius (NTS) play important roles in the regulation of cardiovascular and other autonomic functions. In the present study, we demonstrate an inhibition of brown adipose tissue (BAT) thermogenesis evoked by activation of neurons in the VLM, as well as by neurons in the intermediate NTS, of chloralose/urethane-anesthetized, artificially ventilated rats. Activation of neurons in either rostral VLM or caudal VLM with N-methyl-D-aspartate (12 nmol) reversed the cold-evoked increase in BAT sympathetic nerve activity (SNA), BAT temperature, and end-expired CO 2. Disinhibition of neurons in either VLM or NTS with the GABA A receptor antagonist, bicuculline (30 pmol), reversed the increases in BAT SNA, BAT temperature, and end-expired CO 2 that were elicited 1) by cold defense; 2) during the febrile model of nanoinjection of prostaglandin E 2 into the medial preoptic area; 3) by activation of neurons in the dorsomedial hypothalamus or in the rostral raphe pallidus (rRPa); or 4) by the -opioid receptor agonist fentanyl. Combined, but not separate, inhibitions of neurons in the VLM and in the NTS, with the GABA A receptor agonist, muscimol (120 pmol/site), produced increases in BAT SNA, BAT temperature, and expired CO 2, which were reversed by nanoinjection of glycine (30 nmol) into the rRPa. These findings suggest that VLM and NTS contain neurons whose activation inhibits BAT thermogenesis, that these neurons receive GABAergic inputs that are active under these experimental conditions, and that neurons in both sites contribute to the tonic inhibition of sympathetic premotor neuronal activity in the rRPa that maintains a low level of BAT thermogenesis in normothermic conditions. chemoreceptor; fentanyl; raphe IN MEDIATING NONSHIVERING thermogenesis, brown adipose tissue (BAT) is a site of glucose utilization, lipid oxidation, and energy expenditure that plays an important role in the cold defense response of small mammals and infant primates, but which also contributes to diet-induced thermogenesis (47), and whose reduced function may be a factor in the overweight phenotype of obesity (59). The recent demonstration of significant, metabolically active BAT depots in adult humans (14,43,59) and the potential for dysregulation of BAT energy expenditure in human obesity (14,59) and in models of the wastage syndrome in cachexia (5) have focused interest on the central neural mechanism controlling BAT sympathetic outflow, the primary determinant of BAT thermogenesis and energy consumption (8). The principal pathways for the regulation of BAT thermogenic responses during cold defense and in response to central prostaglandin (PG) E 2 administration have been described (36). In particular, the rostral raphe pallidus (rRPa) is the principal site of BAT sympathetic premotor neurons, and BAT sympathetic outflow is markedly increased by antagonism of GABA A receptors in rRPa (37), presumably mediated by a disinhibition of BAT sympathetic premotor neurons in rRPa....

A hypothalamic circuit that controls body temperature

“…Early observations suggested that glutamatergic neurons may project directly to premotor neurons within the rostral medullary region (rMR) to promote thermogenesis (16)(17)(18). It has also been reported that rMR premotor neurons receive inhibitory inputs from other medullary regions (32,33). Thus, DMD Vglut2 neurons may directly innervate rMR premotor neurons to promote thermogenesis, and DMD Vgat neurons might disinhibit rMR neurons by suppressing their inhibitory inputs.…”

“…DMD glutamatergic neurons may send excitatory input to premotor neurons in the rMR to stimulate thermogenesis (16)(17)(18). DMD GABAergic neurons might disinhibit rMR premotor neurons by suppressing their inhibitory inputs (32,33 Table S1. *P ≤ 0.05; **P ≤ 0.01.…”

Involvement of endogenous hydrogen sulfide (H2S) in the rostral ventrolateral medulla (RVLM) in hypoxia-induced hypothermia

“…NTS projections reach the RVLM (Accorsi-Mendonca et al, 2009;Aicher et al, 1996), a group of neurons extending from the caudal end of facial nucleus to the caudal ventrolateral medulla (Dobbins and Feldman, 1994;Wang et al, 2002) which plays a role in the generation of sympathetic and respiratory outputs (Alheid and McCrimmon, 2008;Smith et al, 2007) and modulates the activity of rostral raphe pallidus which in turn controls nonshivering heat production (brown adipose tissue thermogenesis) (Cao et al, 2010).…”

“…Structures involved in the control of brown adipose tissue thermogenesis, such as the RVLM and the rostral raphe pallidus (Cao et al, 2010), are affected by a number of modulators. Recently, H 2 S, a gaseous transmitter that regulates several biological systems through a number of interconnected mechanisms (Wagner et al, 2009), has been shown to mediate the well-described effect of hypoxia on energy expenditure (Haouzi et al, 2008).…”

“…Rostral ventrolateral medulla (RVLM) is a brainstem region that has been reported to play an inhibitory role in the sympathetic outflow to brown adipose tissue (Cao et al, 2010), a thermogenic tissue whose activity is reduced during exposure to hypoxia (Cannon and Nedergaard, 2004;Gautier, 1996;Hinrichsen et al, 1998;Mortola and Naso, 1997;Mortola et al, 1999). Therefore, taking into consideration that the RVLM may participate in hypoxia-induced hypothermia and that H 2 S modulates RVLM neurons activity (Guo et al, 2011), the present study was undertaken to test the hypothesis that H 2 S endogenously produced in the RVLM plays a modulatory role in hypoxic hypothermia.…”