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Lateral Hypothalamic Regulation of Energy Homeostasis and Sympathetic Outflow: The Role of Leptin and Melanocortin Signaling
Author(s) -
Cruz Eva Nilda Rodriguez,
Morgan Donald A,
Davis Kevin Carroll,
Saito Kenji,
Toth Brandon A,
Martinez Eduardo,
Jiang Jingwei,
Rahmouni Kamal,
Cui Huxing
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb702
Subject(s) - melanocortin , leptin , medicine , endocrinology , energy homeostasis , melanocortin 4 receptor , hypothalamus , leptin receptor , homeostasis , melanocortin receptor , sympathetic nervous system , blood pressure , biology , glucose homeostasis , adipose tissue , melanocortins , kidney , receptor , obesity , insulin resistance
Hypothalamus plays a fundamental role in both body weight homeostasis and sympathetic regulation, but the underlying neural basis of this association remains incompletely understood. Brain leptin and melanocortin systems have emerged as critical regulators of body weight homeostasis, sympathetic nerve activity (SNA) and blood pressure. However, the neural circuits by which leptin and melanocortin regulate SNA and blood pressure have not been fully defined. We have previously identified a unique subpopulation of GABAergic neurons in the lateral hypothalamic area (LHA), a historically recognized “feeding center” in the brain, that coexpress both leptin receptor (LepR) and melanocortin 4 receptor (MC4R), indicating that this unique subset of LHA inhibitory neurons are direct targets of endogenous leptin and melanocortin. Because of a well‐established role of LHA in both feeding and sympathetic regulation, we hypothesized that LHA MC4R signaling pathway may plays a key role in sympathetic overactivity and elevated blood pressure associated with obesity. Here we show that in vivo Cre/loxP system‐mediated re‐expression of endogenous MC4Rs in the LHA of severely obese MC4R‐null mice restores the blunted responses of MC4R agonist MTII‐mediated increase in sympathetic outflow to various beds, including brown adipose tissue, muscle, and kidney, and elevates blood pressure in obese normotensive MC4R‐TB mice without significantly affecting food intake and body weight. Finally, optogenetic and/or chemogenetic stimulation of LHA LepR‐positive neurons (some of which are also MC4R‐positive) suppresses food intake and deceases blood pressure and renal SNA in conscious mice. In conclusion, our findings identify a novel brain circuit by which leptin and melanocortin signaling regulate sympathetic traffics and blood pressure, which may contribute to the development of obesity‐associated hypertension. Support or Funding Information NIH/NHLBI R01 HL127673‐01A1