The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits

Monica M Li; Joseph C Madara; Jennifer S Steger; Michael J Krashes; Nina Balthasar; John N Campbell; Jon M Resch; Nicholas J Conley; Alastair S Garfield; Bradford B Lowell

doi:10.1016/j.neuron.2019.02.028

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The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits

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The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits

Monica M Li, Joseph C Madara, Jennifer S Steger, Michael J Krashes, Nina Balthasar, John N Campbell, Jon M Resch, Nicholas J Conley, Alastair S Garfield and Bradford B Lowell

Neuron (Cambridge, Mass.), Vol.102(3), pp.653-667.e6

05/08/2019

DOI: 10.1016/j.neuron.2019.02.028

PMCID: PMC6508999

PMID: 30879785

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Abstract

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVH population, melanocortin-4 receptor-expressing (PVH ) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVH neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVH ) neurons, which notably lack MC4Rs, function independently and additively with PVH neurons to account for the totality of PVH neuron-mediated satiety. Moreover, PVH neurons are necessary for prevention of obesity in an independent but equipotent manner to PVH neurons. While PVH and PVH neurons both project to the parabrachial complex (PB), they synaptically engage distinct efferent nodes, the pre-locus coeruleus (pLC), and central lateral parabrachial nucleus (cLPBN), respectively. PB-projecting PVH neurons, like PVH neurons, receive input from interoceptive ARC neurons, respond to caloric state, and are sufficient and necessary to control food intake. This expands the CNS satiety circuitry to include two non-overlapping PVH to hindbrain circuits.

Parabrachial Nucleus - metabolism

Paraventricular Hypothalamic Nucleus - physiology

Enkephalins - metabolism

Arcuate Nucleus of Hypothalamus - cytology

Neurons - cytology

Receptor, Melanocortin, Type 4 - metabolism

Satiety Response - physiology

Paraventricular Hypothalamic Nucleus - cytology

Locus Coeruleus - cytology

Basic Helix-Loop-Helix Transcription Factors - metabolism

Neurons - physiology

Neurons - metabolism

Repressor Proteins - metabolism

Arcuate Nucleus of Hypothalamus - metabolism

Locus Coeruleus - physiology

Obesity - physiopathology

Arcuate Nucleus of Hypothalamus - physiology

Parabrachial Nucleus - cytology

Agouti-Related Protein - metabolism

Feeding Behavior - physiology

Protein Precursors - metabolism

Animals

Energy Metabolism

Parabrachial Nucleus - physiology

Paraventricular Hypothalamic Nucleus - metabolism

Mice

Locus Coeruleus - metabolism

Details

Title: Subtitle: The Paraventricular Hypothalamus Regulates Satiety and Prevents Obesity via Two Genetically Distinct Circuits
Creators: Monica M Li - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Joseph C Madara - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Jennifer S Steger - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Michael J Krashes - Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
Nina Balthasar - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
John N Campbell - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Jon M Resch - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Nicholas J Conley - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Alastair S Garfield - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK. Electronic address: agarfield@rhythmtx.com
Bradford B Lowell - Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02215, USA. Electronic address: blowell@bidmc.harvard.edu
Resource Type: Journal article
Publication Details: Neuron (Cambridge, Mass.), Vol.102(3), pp.653-667.e6
DOI: 10.1016/j.neuron.2019.02.028
PMID: 30879785
PMCID: PMC6508999
NLM abbreviation: Neuron
ISSN: 0896-6273
eISSN: 1097-4199
Publisher: United States
Grant note: R01 DK096010 / NIDDK NIH HHS R01 DK111401 / NIDDK NIH HHS R01 DK089044 / NIDDK NIH HHS R01 DK075632 / NIDDK NIH HHS F32 DK103387 / NIDDK NIH HHS P30 DK046200 / NIDDK NIH HHS 14POST20100011 / American Heart Association-American Stroke Association P30 DK057521 / NIDDK NIH HHS
Language: English
Date published: 05/08/2019
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9984065854402771

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