Abstract 010: The Role of Angiotensin AT1A Receptors in Leptin-sensitive Cells in Resting Metabolic Rate Control
The brain renin-angiotensin system (RAS) and leptin contribute to the control of resting metabolic rate (RMR) and their receptors are co-expressed in areas of the brain critical for metabolic control; thus angiotensin and leptin may interact within the brain to regulate RMR and obesity. Inhibition of the brain RAS attenuates sympathetic nerve activity (SNA) responses to leptin, leading us to hypothesize that the brain RAS mediates the RMR effects of leptin. Mice lacking angiotensin AT1Areceptors in leptin receptor-expressing cells (ObRb-Cre x AT1Aflox/flox; “KO”) exhibited normal body weight (15 weeks of age: control n=28, 26.0 ± 0.7, vs KO n=35, 25.8 ± 0.6 g), food intake (control n=12, 3.1 ± 0.15, vs KO n=15, 3.4 ± 0.14 g) and RMR (control n=13, 0.15 ± 0.004, vs KO n=15, 0.16 ± 0.006 kcal/hr) on standard chow diet. Brown adipose SNA responses to acute leptin injection, however, were completely attenuated in KO mice. When maintained on a 45% high fat diet (HFD), KO mice gained significantly more fat mass (control n=35, 5.6 ± 0.4, vs KO n=31, 7.4 ± 0.5 g, P<0.05) and body mass (control, 27.4 ± 0.6, vs KO, 29.6 ± 0.6 g, P<0.05) due to a loss of diet-induced thermogenesis (control n=22, 0.18 ± 0.008, vs. KO n=12, 0.16 ± 0.004 kcal/hr, P<0.05). KO mice exhibited attenuated hypothalamic proopiomelanocortin (POMC) gene expression and partially attenuated RMR responses to alpha-melanocyte stimulating hormone (αMSH; control n=3, 0.25 ± 0.01, vs KO n=7, 0.2 ± 0.01 kcal/hr, P<0.05) indicating that the interaction between leptin and AT1A modulates both αMSH production and action. To localize the site of the brain RAS-leptin interaction, we developed novel multi-transgenic mouse models which expresses GFP via the AT1Apromoter (NZ44, from GenSat) and/or conditional activation of a tdTomato reporter (ROSA-stopflox-tdTomato) in cells expressing the leptin receptor (ObRb-Cre) or agouti-related peptide (AgRP-Cre). Immunohistochemical staining of adrenocorticotropin in brain tissue from NZ44 mice revealed no localization of AT1A to POMC neurons; in contrast, AT1A was strongly localized with AgRP promoter activity. Taken together, these data support a critical role for angiotensin AT1Areceptors on AgRP neurons in the arcuate nucleus in resting metabolic rate control.
Author Disclosures: K.E. Claflin: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; AHA. J.L. Grobe: B. Research Grant (includes principal investigator, collaborator, or consultant and pending grants as well as grants already received); Significant; NIH, AHA, ADA.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2015 by American Heart Association, Inc.