Hypothalamic control of brown adipose tissue thermogenesis

Abstract

It has long been known, in large part from animal studies, that the control of brown adipose tissue (BAT) thermogenesis is insured by the central nervous system (CNS), which integrates several stimuli in order to control BAT activation through the sympathetic nervous system (SNS). SNS-mediated BAT activity is governed by diverse neurons found in brain structures involved in homeostatic regulations and whose activity is modulated by various factors including oscillations of energy fluxes. The characterization of these neurons has always represented a challenging issue. The available literature suggests that the neuronal circuits controlling BAT thermogenesis are largely part of an autonomic circuitry involving the hypothalamus, brainstem and the SNS efferent neurons. In the present review, we recapitulate the latest progresses in regards to the hypothalamic regulation of BAT metabolism. We briefly addressed the role of the thermoregulatory pathway and its interactions with the energy balance systems in the control of thermogenesis. We also reviewed the involvement of the brain melanocortin and endocannabinoid systems as well as the emerging role of steroidogenic factor 1 (SF1) neurons in BAT thermogenesis. Finally, we examined the link existing between these systems and the homeostatic factors that modulate their activities.

Keywords: brown adipose tissue; endocannabinoid; hypothalamus; melanocortin; non-shivering thermogenesis; steroidogenic factor 1.

Figure 1

Hypothalamic control of brown adipose tissue thermogenesis. (A) Schematic and tentative representation of the hypothalamic structures involved in the control of BAT thermogenesis. (B) POA is considered to be a major coordinator of thermoregulation as it receives inputs from thermoreceptors essentially located in the skin. Within the POA, cold appears to signal mainly through the MnPO, where GABAergic neurons inhibit GABAergic neurons of the MPO. On the other hand, warm activates glutamatergic neurons in the MnPO, which activate GABAergic neurons of the MPO. One important relay receiving inputs from the POA to regulate BAT metabolism is the DMH. The GABAergic neurons of the MPO provide a negative tonic inhibition toward glutametergic neurons located in the DMH. DMH neurons project to the rostral ventromedial medulla, apparently to the RPa, amain site of BAT SNS premotor neurons. NPY neurons of the DMH could apparently also negatively affect BAT thermogenesis, possibly by inhibiting glutamatergic neurons located in the DMH itself. There also exists at least three important energy homeostasis pathways for BAT thermogenesis. (C) The melanocortin system is a critical component for the maintenance of energy balance. In the ARC, NPY/AgRP neurons inhibit, while POMC neurons (through the production of α-MSH) activate MC4R neurons located in the PVH. These neurons stimulate BAT thermogenesis. However, their identity is actually unknown. Non-MC4R neurons expressing BDNF were also recently shown to regulate BAT metabolism. (D) The endocannabinoid system represents another important system regulating BAT thermogenesis. We have recently shown that injection of Δ9-THC into the fourth ventricle blunts the thermogenic effects of MTII injected in the PVH. This suggests that MC4R-CB1R neurons located in the PVH regulate BAT metabolism. (E) SF1 neurons of the VMH are also well known to affect BAT thermogenesis. Converging evidence indicates that both AMPK and mTOR signaling are molecularly involved in this fine regulation. The VMH neurons regulating thermogenesis seem to relay through hindbrain structures such as the RPa, OI or Sol. (C–E) It is noteworthy that in addition to interacting together, these hypothalamic systems regulating BAT thermogenesis are modulated by important homeostatic hormones such as leptin and insulin. Abbreviations: 5-HT, serotonine; α-MSH, α-melanocyte-stimulating hormone; Δ9-THC, Δ9-tetrahydrocannabinol; AMPK, AMP-activated protein kinase; ARC, arcuate nucleus; BAT, brown adipose tissue; BDNF, brain-derived neurotrophic factor; CB1R, cannabinoid receptor type 1; DMH, dorsomedial hypothalamus, GABA, gamma-aminobutyric acid; IML, intermediolateral nucleus; LH, lateral hypothalamus; MC4R, melanocortin receptor 4; MnPO, median preoptic area; MPO, medial preoptic area; MTII, melanotan II; mTOR, mechanistic target of rapamycin; NPY, neuropeptide Y; OI, inferior olive; POA, preoptic area; POMC, proopiomelanocortin; PVH, paraventricular hypothalamus; RPa, raphe pallidus; SF1, steroidogenic factor 1; Sol, nucleus of the solitary tract; VMH, ventromedial hypothalamus.