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

• Published in: Neuron (Cambridge, Mass.) Mass.), 2019-05, Vol.102 (3), p.653-667.e6
• Main Authors: Li, Monica M., Madara, Joseph C., Steger, Jennifer S., Krashes, Michael J., Balthasar, Nina, Campbell, John N., Resch, Jon M., Conley, Nicholas J., Garfield, Alastair S., Lowell, Bradford B.
• Format: Article
• Language: English
• Subjects: 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; Brain research; Circuits; DNA methylation; Energy; Energy balance; Energy Metabolism; Enkephalins - metabolism; Feeding Behavior - physiology; Food; Food intake; Hindbrain; Hypothalamus; Locus coeruleus; Locus Coeruleus - cytology; Locus Coeruleus - metabolism; Locus Coeruleus - physiology; Melanocortin; Mice; Neurons; Neurons - cytology; Neurons - metabolism; Neurons - physiology; Obesity; Obesity - physiopathology; Parabrachial nucleus; Parabrachial Nucleus - cytology; Parabrachial Nucleus - metabolism; Parabrachial Nucleus - physiology; Paraventricular Hypothalamic Nucleus - cytology; Paraventricular Hypothalamic Nucleus - metabolism; Paraventricular Hypothalamic Nucleus - physiology; Peptides; Population; Prodynorphin; Protein Precursors - metabolism; Receptor, Melanocortin, Type 4 - metabolism; Repressor Proteins - metabolism; Satiety; Satiety Response - physiology; Software; Statistical analysis
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2019.02.028

SIM1-expressing paraventricular hypothalamus (PVH) neurons are key regulators of energy balance. Within the PVHSIM1 population, melanocortin-4 receptor-expressing (PVHMC4R) neurons are known to regulate satiety and bodyweight, yet they account for only half of PVHSIM1 neuron-mediated regulation. Here we report that PVH prodynorphin-expressing (PVHPDYN) neurons, which notably lack MC4Rs, function independently and additively with PVHMC4R neurons to account for the totality of PVHSIM1 neuron-mediated satiety. Moreover, PVHPDYN neurons are necessary for prevention of obesity in an independent but equipotent manner to PVHMC4R neurons. While PVHPDYN and PVHMC4R 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 PVHPDYN neurons, like PVHMC4R neurons, receive input from interoceptive ARCAgRP 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. [Display omitted] •PVH neurons cause satiety, of which ∼50% is accounted for by PVHMC4R neurons•PVHPDYN neurons are identified as novel satiety neurons that prevent obesity•PVHPDYN and PVHMC4R neurons are distinct and equipotent, producing additive effects•PVHPDYN and PVHMC4R neurons use separate efferent circuits to regulate appetite Li et al. discover that PVHPDYN neurons, additively with PVHMC4R neurons, are responsible for PVH-mediated satiety. Both PVH neurons are distinct, are equipotent, and use parallel projections to different aspects of the parabrachial complex to cause satiety and prevent obesity.