title: Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity.
abstract: Obesity is associated with increased levels of angiotensin-II (Ang-II), which activates angiotensin type 1a receptors (AT1a) to influence cardiovascular function and energy homeostasis. To test the hypothesis that specific AT1a within the brain control these processes, we used the Cre/lox system to delete AT1a from the paraventricular nucleus of the hypothalamus (PVN) of mice. PVN AT1a deletion did not affect body mass or adiposity when mice were maintained on standard chow. However, maintenance on a high-fat diet revealed a gene by environment interaction whereby mice lacking AT1a in the PVN had increased food intake and decreased energy expenditure that augmented body mass and adiposity relative to controls. Despite this increased adiposity, PVN AT1a deletion reduced systolic blood pressure, suggesting that this receptor population mediates the positive correlation between adiposity and blood pressure. Gene expression studies revealed that PVN AT1a deletion decreased hypothalamic expression of corticotrophin-releasing hormone and oxytocin, neuropeptides known to control food intake and sympathetic nervous system activity. Whole-cell patch-clamp recordings confirmed that PVN AT1a deletion eliminates responsiveness of PVN parvocellular neurons to Ang-II, and suggest that Ang-II responsiveness is increased in obese wild-type mice. Central inflammation is associated with metabolic and cardiovascular disorders and PVN AT1a deletion reduced indices of hypothalamic inflammation. Collectively, these studies demonstrate that PVN AT1a regulate energy balance during environmental challenges that promote metabolic and cardiovascular pathologies. The implication is that the elevated Ang-II that accompanies obesity serves as a negative feedback signal that activates PVN neurons to alleviate weight gain.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Annette D
authors.initials: AD
authors.lastname: de Kloet
authors.forename: Dipanwita
authors.initials: D
authors.lastname: Pati
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Helmut
authors.initials: H
authors.lastname: Hiller
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Frazier
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: James P
authors.initials: JP
authors.lastname: Herman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Eric G
authors.initials: EG
authors.lastname: Krause
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000311:Adrenal Glands / Q000378:metabolism; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000473:pathology; D002151:Calorimetry; D002319:Cardiovascular System / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D004326:Drinking / Q000235:genetics; D004435:Eating / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency* / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012965:Sodium Chloride / Q000378:metabolism; D013686:Telemetry
chemical_list: D000804:Angiotensin II; D051792:Basic Helix-Loop-Helix Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D012097:Repressor Proteins; D012965:Sodium Chloride; C101750:Sim1 protein, mouse