T cells and NLRP3 Mediate High Fat Diet-Induced Increases in Blood Pressure and Adiposity in Female and Male Dahl Rats

Abstract

Cardiovascular disease (CVD) is the leading cause of death worldwide in both sexes, with hypertension being an important modifiable factor. To increase the number of people with adequate blood pressure control, a better understanding of the mechanisms controlling the development of hypertension is necessary. Chronic consumption of a high fat diet (HFD) increases blood pressure and adiposity. Furthermore, clinical data suggest that women may be predisposed to worse cardiovascular health in instances of excess adiposity. Thus, these experiments were designed to test the central hypothesis that a HFD will increase blood pressure and adiposity more in females vs males. Sprague Dawley rats were resistant to HFD-induced increases in blood pressure or fat mass. Conversely, 10 weeks of HFD treatment increased blood pressure, fat mass, and adipose tissue weight in female and male Dahl Wild Type (WT) rats. This was accompanied by a pro-hypertensive T cell profile in both sexes. This finding pointed to a role for T cells in mediating the morbidity observed, T cell-deficient rats were utilized. T cell knock out (KO) blunted the HFD-induced hypertension in both sexes, but only the HFD-induced increase in adiposity in males. Due to the observed protective role of T cell KO, it was crucial to determine what could be activating T cells. NLRP3 is a pattern recognition receptor which activates T cells and adipogenesis, NLRP3 deficient rats were randomized to a Control (Ctrl) or HFD treatment. NLRP3 KO blunted the HFD-induced adiposity in both sexes. It is well known that free fatty acids (FFAs) can activate NLRP3, so a FFA panel was performed in Dahl WT animals. Females had a more pro-hypertensive FFA profile. The Dahl WT rat is a good model to use to study the loss of protection of females that are on a HFD. Additionally, these data demonstrate that T cells and NLRP3 are playing sex-specific roles to promote the HFD-induced increases in adiposity and blood pressure. Finding sex-specific mechanisms that mediate these morbidities will reduce the number of people that develop hypertension and subsequently, CVD, the number one killer of both men and women in the US.