A Novel Model of Hyperphagia, Obesity, and Endothelial Dysfunction in Mice using a Brain Targeting Adeno-Associated Virus

Abstract

Obesity is a major risk factor for type 2 diabetes mellitus and cardiovascular diseases (CVD) such as atherosclerosis, hypertension and stroke, which account for a majority of worldwide deaths. The complications arising from excess adiposity are multiple and cumulative and thus, animal models are critical to interrogate the mechanisms arising from obesity that contribute to vascular disease. The commonly used models of obesity in mice, namely those with disturbed leptin signaling ( db/db, ob/ob) and use of high fat diets (HFD) mimic aspects of human obesity including increased adiposity, and metabolic and vascular derangement. However, these models also have substantial limitations including: 1) whole body loss of leptin signaling, 2) infertility, a major barrier to generating complex genetic obese mouse models, 3) hyperphagia from birth leading to an obesogenic milieu throughout development, 4) early onset of metabolic derangement inconsistent with the majority of human disease, and 5) HFD fed mice take months to develop a mild form of obesity and do so solely through increased dietary fat consumption outside of the range of normal human diet and not through hyperphagia, a key hallmark of human obesity. To address these limitations, while maintaining the strengths of the aforementioned models, we generated a blood brain barrier crossing AAV (AAV-PHP.eB) that expresses Agouti related peptide (AgRP) in the brains of C57BL/6J mice when administered systemically. Retro-orbital administration of AgRP-AAV.PHP.eB to 8-week-old mice resulted in the expression of AgRP in the brain, the onset of robust hyperphagia within 1 week of injection, and sustained weight gain to a median of 63.1±2.1g. Although male AgRP-AAV mice exhibited metabolic dysfunction as shown by increases in HbA1c, insulin, lipids and leptin at 20 weeks, the magnitude of these changes were less pronounced versus previous findings in db/db mice, suggesting a slower progression metabolic syndrome which is more in line with prediabetic humans. This metabolic phenotype was accompanied by a profound microvascular endothelial dysfunction in mesenteric arteries as determined by reduced dilation to acetylcholine. Strengths of this model include: 1) temporal control the onset of obesity, 2) it is effective in both males and females, 3) it does not depend on a restricted diet with the advantage that it can be combined with changes in diet, 4) AgRP expression is largely restricted to the brain, 5) leptin and leptin receptors are intact, and 6) it can easily be combined with most mouse genetic models without laborious breeding strategies to circumvent infertility. Supported by National Institutes of Health (NIH) 1F31HL154646 (CAP), 1F31HL165916 (HGS), R01HL147159 (DS, DF), HL125926-05A1 (DF) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.