Deletion of brain‐specific isoform of renin (renin‐b) increases resting metabolic rate by stimulating brown adipose tissue sympathetic nerve activity

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Activation of the brain renin‐angiotensin system (RAS) stimulates energy expenditure through increasing sympathetic nerve activity (SNA). In the brain, the renin gene is transcribed from an alternative promoter‐first exon resulting in a product that lacks the signal peptide and a third of the prosegment. This product, termed renin‐b, is highly brain specific and likely remains intracellular. Deletion of renin‐b induces central RAS activation and hypertension, indicating that renin‐b is a negative regulator of the brain RAS. We hypothesize that genetic deletion of renin‐b interferes with the control of metabolism and energy expenditure by inducing brown adipose tissue (BAT) SNA and enhanced insulin sensitivity. We generated a mouse model carrying a selective loss of renin‐b (Renin‐bNull) while preserving the classical renin isoform expressed in the kidney (renin‐a). Resting metabolic rate was assessed by respirometry. Basal BAT SNA was evaluated using direct multifiber recording of SNA subserving BAT. Fasted mice were subjected to glucose tolerance test (GTT) and insulin tolerance test (ITT). Renin‐bNull mice exhibited increased resting metabolic rate in comparison to their control littermates (0.156 ± 0.005 kcal/h in Renin‐bNull vs. 0.145 ± 0.003 kcal/h in control littermates, p<0.015, mean ± SEM). Under basal conditions, Renin‐bNull mice do not show differences in body weight, food consumption, and physical activity. However, weight gain was attenuated in male but not female Renin‐bNull in response to high fat diet (36.8 ± 1.2 in male Renin‐bNull vs. 41.9 ± 1.4 in male control, p<0.03). The analysis of the area under the curve (AUC) in GTT revealed mild but significant glucose intolerance in Renin‐bNull in comparison to control (152.5 ± 20.9 in Renin‐bNull vs. 93.0 ± 14.3 in control, p<0.03). However, there were no significant differences in the AUC in the ITT between Renin‐bNull and the control (174.3 ± 12.8 in Renin‐bNull vs. 207.0 ± 12.8 in control, p=0.077). Deletion of renin‐b induced an increase in SNA in BAT (40.8 ± 3.1 in Renin‐bNull vs. 27.2 ± 3.1 in control, p<0.003) and this was associated with an increase in uncoupled protein 1 (UCP1) protein expression in BAT (2.1 ± 0.5 fold increase in Renin‐bNull vs. control, p<0.05). These data suggest that renin‐b is involved in maintaining energy homeostasis likely by preventing central RAS activation. The activation of BAT SNA and the subsequent UCP1 overexpression are likely to be mechanistically involved in the increased energy expenditure observed in Renin‐bNull mice. Downregulation of renin‐b and the consequent brain RAS activation may be an important pathophysiological mechanism involved not only in the development of neurogenic hypertension, but also in obesity and other metabolic diseases.Support or Funding InformationNIH and AHA