Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake

• Published in: PLoS biology Vol. 16; no. 4; p. e2004399
• Main Authors: Jeong, Jae Hoon, Lee, Dong Kun, Liu, Shun-Mei, Chua, Jr, Streamson C, Schwartz, Gary J, Jo, Young-Hwan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.04.2018; Public Library of Science (PLoS)
• Subjects: Activation; Animals; Appetite; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - cytology; Arcuate Nucleus of Hypothalamus - drug effects; Arcuate Nucleus of Hypothalamus - metabolism; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biology and Life Sciences; Body temperature; Capsaicin; Capsaicin - pharmacology; Capsaicin receptors; Channelrhodopsins - genetics; Channelrhodopsins - metabolism; CRISPR; Data collection; Depolarization; Eating - drug effects; Eating - genetics; Electrophysiology; Endocrinology; Enhancer Elements, Genetic; Enhancers; Female; Fitness equipment; Fluorescence; Food; Food intake; Gene expression; Gene Expression Regulation; Gene Knock-In Techniques; Gene Knockout Techniques; Genes, Reporter; Hypothalamus; Immunohistochemistry; Ion channels; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Medicine; Medicine and Health Sciences; Melanocortin; Mice; Mice, Transgenic; Neural circuitry; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Optogenetics; Physical Conditioning, Animal; Physiological aspects; Physiology; Polymerase chain reaction; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; Proteins; Receptors; Receptors, Melanocortin - genetics; Receptors, Melanocortin - metabolism; Research and Analysis Methods; Reverse transcription; Rodents; Running; Signal Transduction; Single-Cell Analysis; Temperature; Temperature effects; Transient receptor potential proteins; TRPV Cation Channels - agonists; TRPV Cation Channels - deficiency; TRPV Cation Channels - genetics; Viruses; Weight control; Yellow fluorescent protein; New York; United States > US
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.2004399

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.