The brain renin‐angiotensin system promotes a negative energy balance in mice

Abstract

The role of the renin‐angiotensin system (RAS) in the control of energy homeostasis has long been debated, and evidence suggests opposing actions of the central versus the circulating and adipose RAS. We previously developed double‐transgenic (sRA) mice consisting of the human renin gene under the transcriptional control of the neuron‐specific synapsin promoter, and human angiotensinogen under the control of its own endogenous promoter, which results in a CNS‐specific over‐activation of the RAS. Here, we investigated the hypothesis that a centrally overactive RAS would increase energy utilization, and possibly decrease food intake. sRA mice (n=8) exhibited a sustained significant (15%, P<0.001) decrease in body mass compared to littermate controls, which was accompanied by a significantly increased metabolic rate during both sleep (20%, P<0.001) and stationary wakefulness (18%, P=0.002) when assessed indirectly through oxygen consumption (ages 10–12 weeks). sRA mice paradoxically exhibited increased food consumption (20%, P=0.005). Together, these results indicate a negative energy balance in sRA mice, which is predominantly mediated through increased energy expenditure. These findings prompt further studies into the CNS‐RAS in metabolic disorders such as diabetes and the metabolic syndrome. This work was supported by grants (CDS) and postdoctoral fellowships (JLG, CLG) from the NIH and the APS.