A neural basis for melanocortin-4 receptor-regulated appetite.
Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Centre for Integrative Physiology, Hugh Robson Building, University of Edinburgh, Edinburgh, UK.
Alastair S
AS
Garfield
1] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
Chia
C
Li
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Joseph C
JC
Madara
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Bhavik P
BP
Shah
1] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
Emily
E
Webber
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Jennifer S
JS
Steger
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
John N
JN
Campbell
Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Oksana
O
Gavrilova
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Charlotte E
CE
Lee
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
David P
DP
Olson
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Joel K
JK
Elmquist
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Bakhos A
BA
Tannous
1] Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. [2] National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, USA.
Michael J
MJ
Krashes
1] Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. [2] Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA.
Bradford B
BB
Lowell
D054369:Agouti-Related Protein / Q000502:physiology; D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001066:Appetite / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005508:Food Deprivation; D005518:Food Preferences / Q000187:drug effects; D006815:Hunger / Q000502:physiology; D051379:Mice; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000502:physiology; D011333:Pro-Opiomelanocortin / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D012527:Satiation / Q000502:physiology
D054369:Agouti-Related Protein; D019440:Anti-Obesity Agents; D044105:Receptor, Melanocortin, Type 4; D011333:Pro-Opiomelanocortin