Cardiovascular disease (CVD) is a major contributor to US morbidity and mortality; significantly increasing chronic disabilities and shortening life expectancy. Obesity is a major driver of CVD and the rapid rise in the numbers of obese individuals portends an alarming societal burden. The etiology of CVD in obesity is incompletely understood and potential interventions to break the links between weight gain and vascular disease remain a critical barrier to treatment. Modeling complex disorders such as obesity in mice is an imperfect science but mouse models lacking leptin (ob/ob) or leptin receptors (db/db) mimic key aspects of human disease such as hyperphagia, overt obesity and vascular dysfunction. Limitations of these models include deficits in leptin signaling (not widely seen in humans), infertility which is a barrier to making compound genetic models and little to no temporal control of onset. To address these concerns, we hypothesized that delivery of AgRP, an orexigenic signaling molecule, to the brain of a C57BL6 mouse via a brain-specific AAV would precipitate hyperphagia and obesity and recapitulate the vascular dysfunction exhibited by other hyperphagic models. Administration of this AAV elicits tightly restricted expression of AgRP in the brain and a significant (p=0.002) hyperphagic response on a standard chow diet. This leads to subsequent robust weight gain to a final weight of 63.1±2.1g, comparable to that of the db/db model. Pressure myography of mesenteric microvessels from lean control and obese AgRP AAV mice showed significant (p<0.001) impairment in endothelial dependent relaxation in the vessels from obese animals. Overall our findings with this model recapitulate the obesity and vascular dysfunction seen in other severely obese mouse models while providing increased flexibility and temporal control.
|Original language||English (US)|
|Journal||FASEB journal : official publication of the Federation of American Societies for Experimental Biology|
|State||Published - May 1 2022|
ASJC Scopus subject areas
- Molecular Biology