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

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

Neuron. 2019 May 8;102(3):653-667.e6. doi: 10.1016/j.neuron.2019.02.028. Epub 2019 Mar 14.

Affiliations

¹ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
³ 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.
⁴ 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.

Abstract

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVH^SIM1 population, melanocortin-4 receptor-expressing (PVH^MC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVH^SIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVH^PDYN) neurons, which notably lack MC4Rs, function independently and additively with PVH^MC4R neurons to account for the totality of PVH^SIM1 neuron-mediated satiety. Moreover, PVH^PDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVH^MC4R neurons. While PVH^PDYN and PVH^MC4R 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^PDYN neurons, like PVH^MC4R neurons, receive input from interoceptive ARC^AgRP 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Agouti-Related Protein / metabolism
Animals
Arcuate Nucleus of Hypothalamus / cytology
Arcuate Nucleus of Hypothalamus / metabolism
Arcuate Nucleus of Hypothalamus / physiology
Basic Helix-Loop-Helix Transcription Factors / metabolism
Energy Metabolism
Enkephalins / metabolism
Feeding Behavior / physiology*
Locus Coeruleus / cytology
Locus Coeruleus / metabolism
Locus Coeruleus / physiology
Mice
Neurons / cytology*
Neurons / metabolism
Neurons / physiology
Obesity / physiopathology*
Parabrachial Nucleus / cytology
Parabrachial Nucleus / metabolism
Parabrachial Nucleus / physiology
Paraventricular Hypothalamic Nucleus / cytology*
Paraventricular Hypothalamic Nucleus / metabolism
Paraventricular Hypothalamic Nucleus / physiology
Protein Precursors / metabolism
Receptor, Melanocortin, Type 4 / metabolism
Repressor Proteins / metabolism
Satiety Response / physiology*

Substances

Agouti-Related Protein
Agrp protein, mouse
Basic Helix-Loop-Helix Transcription Factors
Enkephalins
MC4R protein, mouse
Protein Precursors
Receptor, Melanocortin, Type 4
Repressor Proteins
Sim1 protein, mouse
preproenkephalin

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

Authors

Affiliations

Abstract

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MeSH terms

Substances

Grants and funding