Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis

Abstract

The preoptic area (POA) regulates body temperature, but is not considered a site for body weight control. A subpopulation of POA neurons express leptin receptors (LepRb POA neurons) and modulate reproductive function. However, LepRb POA neurons project to sympathetic premotor neurons that control brown adipose tissue (BAT) thermogenesis, suggesting an additional role in energy homeostasis and body weight regulation. We determined the role of LepRb POA neurons in energy homeostasis using cre-dependent viral vectors to selectively activate these neurons and analyzed functional outcomes in mice. We show that LepRb POA neurons mediate homeostatic adaptations to ambient temperature changes, and their pharmacogenetic activation drives robust suppression of energy expenditure and food intake, which lowers body temperature and body weight. Surprisingly, our data show that hypothermia-inducing LepRb POA neurons are glutamatergic, while GABAergic POA neurons, originally thought to mediate warm-induced inhibition of sympathetic premotor neurons, have no effect on energy expenditure. Our data suggest a new view into the neurochemical and functional properties of BAT-related POA circuits and highlight their additional role in modulating food intake and body weight.

A hypothalamic circuit that controls body temperature

“…Although a similar (or stronger) effect was observed after activation of glutamatergic neurons in several preoptic subregions [MPA (6), and MPO (5)], activation of GABAergic neurons in these areas has a small effect on T core , and the role of GABAergic neurons in the vLPO was not studied previously. We found that activation of GABAergic neurons in the vLPO is sufficient to induce hypothermia ( Fig.…”

“…However, although recent data have identified some of the neural substrates for temperature sensing (5,6), components of the neural circuit(s) that respond to thermal challenges have not been Significance Thermal homeostasis is essential for survival in mammals. Although it is known that temperature-sensitive neurons in the hypothalamus can control body temperature, the precise neural types and dynamics of neurons responding to changes in environmental temperature are not well defined.…”

“…For example, there are conflicting data concerning the potential role of GABAergic neurons in the POA (2,5,6). To identify these key neural populations, we characterized the pattern of cFos activation following a thermal challenge (SI Appendix, Fig.…”

“…Thermosensitive transient receptor potential channel M2 (TRPM2), which is expressed in the POA, may be part of the heat sensor in WSNs that can limit fever and induce hypothermia (5). Furthermore, activation of glutamatergic neurons in several POA subareas results in severe hypothermia, whereas activation of subsets of POA GABAergic neurons has been found to have only a minimal or no effect on T core (5,6). However, the precise nature of the POA projections that play a role in suppressing thermogenesis have not been elucidated.…”

Leptin and brain–adipose crosstalks

“…For example, many hypothalamic neurons involved in regulating non-shivering thermogenesis are also leptin sensitive 112 , and leptin-deficient mice have a lowered core temperature when housed in conditions below 113 . Exogenous hypothalamic leptin also enhances glucose uptake by BAT and raises BAT temperature 114–117 .…”