Angiotensin type 1a receptor within the hypothalamic arcuate nucleus is required to maintain programmed cardiometabolic phenotypes after early-life sodium restriction

Extremely premature birth is a risk factor for sodium (Na) depletion due to renal immaturity and confers a life-long risk for cardiometabolic disease. We previously demonstrated that dietary Na restriction during hypothalamic maturation programs long-lasting changes in the autonomic nervous system and energy homeostasis via the renin-angiotensin system (RAS). Given that RAS signaling via the angiotensin II type 1 receptor (AT1R) in the hypothalamic arcuate nucleus (ARC) plays a role in the integrative control of thermogenic autonomic nerve activity, we hypothesized that early-life Na restriction programs cardiometabolic function specifically via alterations in ARC AT1R signaling. To test this hypothesis, mice harboring a conditional allele for the endogenous AT1R gene (Agtr1aFLOX/FLOX mice), were provided a customized low Na (0.04% Na) 2920x diet between 3 and 6 weeks of age, then returned to a standard (0.15% Na) diet. At 8 weeks of age, an AAV encoding Cre-recombinase (n = 9M + 8F) or GFP (n = 10M + 8F) was bilaterally microinjected into the ARC to induce AT1R knockout within the ARC. After 2 weeks, deletion of AT1R from the ARC caused a significant increase in body mass compared to controls (GFP: +1.29±0.18 vs. Cre: +3.55±0.36 Δ grams body mass, p< 0.0001). Changes in total body mass were driven primarily by increases in fat mass (GFP: +0.39±0.14 vs. Cre: +1.96±0.23 Δ grams fat mass, p< 0.0001). No differences in food intake (GFP: 3.69±0.16 vs. Cre: 3.79±0.17 grams/24 hours) or digestive efficiency (GFP: 83.31±0.34 vs. Cre: 82.83±0.64 % kcals consumed) were observed. 24-hour average energy expenditure, assessed via gas respirometry, was unchanged despite the significant increase in body mass (GFP: 0.45±0.01 vs. Cre: 0.45±0.01 kcal/h). These data indicate that AT1R specifically within the ARC is required to maintain energy expenditure phenotypes programmed by early-life Na restriction. Ongoing experiments assessing the effects of Cre alone and conditional Agtr1a deletion in adult mice without a history of Na restriction will further clarify how AT1R signaling contributes to metabolic control, and whether early-life Na restriction exaggerates this control. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.