Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis

• Published in: Nature neuroscience Vol. 19; no. 10; pp. 1341 - 1347
• Main Authors: Zhang, Xiaobing, van den Pol, Anthony N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 13/51; 631/378/1488/1562; 631/378/1488/393; 631/378/1697; 631/378/3920; 64/110; 64/60; 96/35; Agouti-Related Protein - metabolism; Analysis; Animal Genetics and Genomics; Animals; Arcuate Nucleus of Hypothalamus - metabolism; Arcuate Nucleus of Hypothalamus - physiology; Behavioral Sciences; Biological Techniques; Biomedicine; Body weight; Body Weight - physiology; Dopamine; Dopamine - metabolism; Dopamine - physiology; Eating - physiology; Energy; Energy Metabolism; Female; Food; GABA; gamma-Aminobutyric Acid - metabolism; Ghrelin - physiology; Health aspects; Homeostasis; Hydroxylases; Male; Mice; Neural Inhibition - physiology; Neurobiology; Neurons; Neurons - metabolism; Neurons - physiology; Neuropeptide Y - metabolism; Neuropeptides; Neurosciences; Obesity; Paraventricular Hypothalamic Nucleus - physiology; Peptides; Pro-Opiomelanocortin - metabolism; Transgenic animals; Tyrosine 3-Monooxygenase - metabolism; Tyrosine 3-Monooxygenase - physiology
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.4372

The authors show that hypothalamic neurons that synthesize tyrosine hydroxylase regulate food intake and body weight. By a combination of dopamine and GABA release, these neurons modulate the activity of both pro-opiomelanocortin neurons and paraventricular nucleus neurons that also contribute to energy homeostasis. Energy homeostasis, food intake, and body weight are regulated by specific brain circuits. Here we introduce an unexpected neuron, the tyrosine hydroxylase (TH) neuron of the arcuate nucleus (ARC), that we show makes an orexigenic contribution. Optogenetic stimulation of mouse ARC TH neurons increased food intake; attenuating transmitter release reduced body weight. Optogenetic stimulation of ARC TH cells inhibited pro-opiomelanocortin (POMC) neurons through synaptic mechanisms. ARC TH cells project to the hypothalamic paraventricular nucleus; optogenetic stimulation of ARC TH axons inhibited paraventricular nucleus neurons by dopamine and GABA co-release. Dopamine excited orexigenic neurons that synthesize agouti-related peptide and neuropeptide Y but inhibited anorexigenic neurons that synthesize POMC, as determined by whole cell recording. Food deprivation increased c-fos expression and spike frequency in ARC TH neurons. The gut peptide ghrelin evoked direct excitatory effects, suggesting these neurons monitor metabolic cues. Together these data support the view that ARC TH cells play an unrecognized and influential positive role in energy homeostasis.