Cardiometabolic dysfunction in an ovarian failure model of menopause: Role of angiotensin AT1R in AgRP neurons
Description: Obesity is the primary risk factor for hypertension, and the AHA has stated that these two diseases are the primary impediments to ongoing improvements in cardiovascular health. Although various interventions exist to induce weight loss, very few people keep weight off long-term. This weight regain appears to mechanistically be due to the suppression, or adaptation, of resting metabolic rate (RMR). Angiotensin II (ANG) and its type 1 receptor (AT1R) in the brain are important for blood pressure control. Our group previously discovered AT1R on a unique neuron subtype (Type 1 Agouti-related peptide neurons) in the hypothalamus is also important for RMR control. While AT1R in this neuron type normally inhibits the cell via a Gi cascade, diet-induced obesity causes AT1R to spontaneously undergo a ‘signal switch’ and start stimulating the cell via Gq. This AT1R signal switching appears to represent a molecular mechanism of RMR adaptation. Notably, we discovered that healthy young female mice are resistant to AT1R signal switching, just as they are resistant to RMR adaptation and diet-induced obesity. Menopause in humans is associated with RMR adaptation, weight gain, and increased cardiovascular risk. Estrogen is known to be protective against cardiometabolic disease, leading to the hypotheses that estrogen may prevent AT1R signal switching and its sequalae, and by extension, that loss of estrogen during menopause may precipitate signal switching and thereby RMR adaptation and weight gain. Rodents do not exhibit a natural menopause, but chemical treatment with 4-vinylcyclohexene diepoxide (VCD) induces progressive ovarian failure, thus providing a model platform to study a menopause-like state. Preliminary data demonstrate that VCD treatment in mice causes a significant decrease in RMR and subsequently, increased adiposity. Proposed studies will dissect (i) the modulatory effects of estrogen upon AT1R second-messenger coupling in AgRP neurons, and (ii) the consequences of chemogenetic Gi versus Gq activation in these neurons upon RMR control during a menopause-like state. We will leverage an array of advanced cardiometabolic phenotyping, electrophysiological, and chemogenetic approaches, and novel genetically-modified mouse models. Findings of this work will importantly contribute to our understanding of RMR control, and our understanding of the cellular and molecular basis of increased cardiometabolic risks that are associated with menopause.
Funder: American Heart Association
Amount: $159,200
Funding type: fellowship
Funder scheme: Postdoctoral Fellowship
Start date: 2026-05-01
End date: 2028-04-30
Investigators: Natalia Mathieu, Natalia Mathieu
Institution: The Medical College of Wisconsin, Inc.
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Funded outputs count: 2
Funder award ID: 26POST1550521
OpenAlex ID: G770436845