Abstract
Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1)-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, electrophysiology, TRPV1 knock-out (KO), and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5) carrying a Cre-dependent channelrhodopsin-2 (ChR2)–enhanced yellow fluorescent protein (eYFP) expression cassette under the control of the two neuronal POMC enhancers (nPEs). Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.
Highlights
Body temperature changes according to the circadian rhythm, physical activities, and external factors such as food intake [1,2,3]
As exercise is accompanied by increased body temperature, we hypothesized that a rise in body temperature during exercise plays a role in reducing food intake
We examined whether arcuate nucleus of the hypothalamus (ARC) POMC neurons respond to the selective transient receptor potential vanilloid 1 receptor (TRPV1) receptor agonist capsaicin [24,25,26]
Summary
Body temperature changes according to the circadian rhythm, physical activities, and external factors such as food intake [1,2,3]. The transient receptor potential vanilloid subfamily members 1–4 (TRPV1, 2, 3, and 4) in peripheral sensory neurons play a role in accurately sensing ambient temperature and in adapting to environmental temperature changes through behavioral and physiological responses [4,5,6,7,8,9]. In the early 1960s, Nakayama and colleagues showed that local hypothalamic heating from 36.7 ̊C to 38.7 ̊C increases hypothalamic neuronal activity [10], suggesting that, like peripheral sensory neurons, hypothalamic neurons are able to respond to changes in temperature, possibly via activation of temperature-sensitive transient receptor potential vanilloid (TRPV) channels. TRPV1-expressing vasopressin neurons show temperaturesensitive inward currents at temperatures above 35 ̊C [13,15,16], which is in contrast to the prior findings that recombinant TRPV1 receptors are activated only by noxious temperatures (>42 ̊C) [4]. We sought to determine whether ARC POMC neurons express temperaturesensitive TRPV1 receptors
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