Chronic intracerebroventricular infusion of angiotensin II causes dose- and sex-dependent effects on intake behaviors and energy homeostasis in C57BL/6J mice

Abstract

The renin-angiotensin system (RAS) within the brain is implicated in control of fluid and electrolyte balance, autonomic functions, blood pressure, and energy expenditure. Mouse models are increasingly used to explore these mechanisms, however, sex and dose dependencies of effects elicited by chronic intracerebroventricular (ICV) angiotensin II (Ang-II) infusion have not been carefully established in this species. To examine the interactions among sex, body mass, and ICV Ang-II upon ingestive behaviors and energy balance, young adult C57BL/6J mice of both sexes were studied in a multiplexed metabolic phenotyping system (Promethion) during chronic infusion of Ang-II (0, 5, 20, or 50 ng/h). At these infusion rates, Ang-II caused accelerating dose-dependent increases in drinking and total energy expenditure in male mice, but female mice exhibited a complex biphasic response with maximum responses at 5 ng/h. Body mass differences did not account for sex-dependent differences in drinking behavior or total energy expenditure. In contrast, resting metabolic rate was similarly increased by ICV Ang-II in a dose-dependent manner in both sexes after correction for body mass. We conclude that chronic ICV Ang-II stimulates water intake, resting and total energy expenditure in male C57BL/6J mice following straightforward accelerating dose-dependent kinetics, but female C57BL/6J mice exhibit complex biphasic responses to ICV Ang-II. Further, control of resting metabolic rate by Ang-II is dissociable from mechanisms controlling fluid intake and total energy expenditure. Future studies of the sex-dependency of Ang-II within the brain of mice must be designed to carefully consider the biphasic responses that occur in females.

Cardiometabolic Effects of DOCA-Salt in Mice Depend on Ambient Temperature

“…18 Similar effects are observed with chronic intracerebroventricular infusion of angiotensin II in mice. 33 Notably all of those studies were performed in mice housed at RT, and, therefore, the current study prompts questions regarding the locations and mechanisms by which temperature sensation and signaling of AT 1 R within the hypothalamus intersect to coordinate appropriate thermoregulatory responses. For example, these results prompt the hypotheses that angiotensinergic signaling within the brain may act to modify either the relationship (ie, sensitivity or gain) between ambient temperature detection and its perception or the triggering of physiological responses to such a stimulus.…”

Neural Circuits Underlying Reciprocal Cardiometabolic Crosstalk: 2023 Arthur C. Corcoran Memorial Lecture

“…128 Moreover, direct central administration of Ang II (angiotensin II) causes a robust increase in energy expenditure, leading to significant weight loss in rodents. [129][130][131][132] Conversely, mice lacking the AT1aR (Ang II type 1a receptor) in the PVN displayed decreased energy expenditure, which resulted in excess adiposity. 133 The influence of the neuronal RAS on energy balance may relate to its role in mediating leptin-triggered regulation of energy homeostasis.…”