Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism

keisuke shinohara, Pablo Nakagawa, Javier Gomez, Donald A. Morgan, Nicole K. Littlejohn, Matthew D. Folchert, Benjamin J. Weidemann, Xuebo Liu, Susan A. Walsh, Laura L. Ponto, Kamal Rahmouni, Justin L. Grobe, Curt D. Sigmund

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Abstract

The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after deoxycorticosterone acetate-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

Original languageEnglish
Pages (from-to)990-997
Number of pages8
JournalHypertension
Volume70
Issue number5
DOIs
Publication statusPublished - Nov 1 2017

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Renin
Drinking
Brain
Renin-Angiotensin System
Basal Metabolism
Desoxycorticosterone
Brown Adipose Tissue
Insulin Resistance
Protein Isoforms
Acetates
Salts
Glucose
Thermogenesis
High Fat Diet
Dehydration
Homeostasis
Eating
Body Weight
Diet
Hypertension

All Science Journal Classification (ASJC) codes

  • Internal Medicine

Cite this

shinohara, K., Nakagawa, P., Gomez, J., Morgan, D. A., Littlejohn, N. K., Folchert, M. D., ... Sigmund, C. D. (2017). Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. Hypertension, 70(5), 990-997. https://doi.org/10.1161/HYPERTENSIONAHA.117.09923

Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. / shinohara, keisuke; Nakagawa, Pablo; Gomez, Javier; Morgan, Donald A.; Littlejohn, Nicole K.; Folchert, Matthew D.; Weidemann, Benjamin J.; Liu, Xuebo; Walsh, Susan A.; Ponto, Laura L.; Rahmouni, Kamal; Grobe, Justin L.; Sigmund, Curt D.

In: Hypertension, Vol. 70, No. 5, 01.11.2017, p. 990-997.

Research output: Contribution to journalArticle

shinohara, K, Nakagawa, P, Gomez, J, Morgan, DA, Littlejohn, NK, Folchert, MD, Weidemann, BJ, Liu, X, Walsh, SA, Ponto, LL, Rahmouni, K, Grobe, JL & Sigmund, CD 2017, 'Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism', Hypertension, vol. 70, no. 5, pp. 990-997. https://doi.org/10.1161/HYPERTENSIONAHA.117.09923
shinohara K, Nakagawa P, Gomez J, Morgan DA, Littlejohn NK, Folchert MD et al. Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. Hypertension. 2017 Nov 1;70(5):990-997. https://doi.org/10.1161/HYPERTENSIONAHA.117.09923
shinohara, keisuke ; Nakagawa, Pablo ; Gomez, Javier ; Morgan, Donald A. ; Littlejohn, Nicole K. ; Folchert, Matthew D. ; Weidemann, Benjamin J. ; Liu, Xuebo ; Walsh, Susan A. ; Ponto, Laura L. ; Rahmouni, Kamal ; Grobe, Justin L. ; Sigmund, Curt D. / Selective Deletion of Renin-b in the Brain Alters Drinking and Metabolism. In: Hypertension. 2017 ; Vol. 70, No. 5. pp. 990-997.
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AU - Weidemann, Benjamin J.

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N2 - The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after deoxycorticosterone acetate-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

AB - The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after deoxycorticosterone acetate-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

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