title: A brain leptin-renin angiotensin system interaction in the regulation of sympathetic nerve activity.
abstract: The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.
authors.affiliation: Center on Functional Genomics of Hypertension, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Hilzendeger
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.forename: Leonard
authors.initials: L
authors.lastname: Brooks
authors.forename: David
authors.initials: D
authors.lastname: Dellsperger
authors.forename: Xuebo
authors.initials: X
authors.lastname: Liu
authors.forename: Justin L
authors.initials: JL
authors.lastname: Grobe
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Allyn L
authors.initials: AL
authors.lastname: Mark
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000294:innervation; D000804:Angiotensin II / Q000096:biosynthesis; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000502:physiology*; D002216:Captopril / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D004435:Eating / Q000187:drug effects / Q000523:psychology; D017353:Gene Deletion; D020738:Leptin / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology*; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C544066:Agtr1a protein, mouse; C544067:Agtr1a protein, rat; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D020738:Leptin; D044140:Receptor, Angiotensin, Type 1; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; D000804:Angiotensin II; D000521:alpha-MSH; D003346:Corticotropin-Releasing Hormone; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D019808:Losartan