Perivascular Adipose Tissue Remodeling Modulates Vascular Mitochondrial Metabolism

Diabetes increases cardiovascular disease (CVD) risk. Diabetes-mediated vascular pathology proceeds differently in men and women. We reported that housing rats at thermoneutral (30°C, TN) conditions alters perivascular adipose tissue (PVAT) phenotype. We also observed related abnormalities in vasoreactivity and mitochondrial function with sex-differences. We hypothesized that TN-mediated PVAT phenotypic transformation alters brown adipose tissue (BAT) regulator PRDM16, fatty acid composition, fatty acid (FA) transporter FATP1, and mitochondrial lipid oxidation in a sex-dependent manner. Male and female Wistar rats were housed at room temperature (24°C, RT) or TN for 16 weeks. Endpoints included PVAT phenotypic characterization, RNA seq analysis, and PVAT mitochondrial respiration. PVAT phenotype was morphologically different between TN and RT rats, with rats housed at TN having 19.7% less BAT phenotype overall (p<0.05). UCP-1 expression was lower in animals housed at TN (p=0.06). PRDM16 was significantly dampened in all animals at TN (p<0.05), and notably decreased in males at TN (80.6%, p<0.05). Loss of BAT markers was associated with changes in FA regulation. Genomic expression of FATP1 was lower in all animals at TN, more prominently in females. Palmitoleic and arachidonic acids were significantly lower in TN females (48.5% and 15.5%, respectively, p<0.05) and males (63.0% and 40.1%, respectively, p<0.05). PVAT of all animals housed at TN showed mitochondrial respiration significantly diminished in lipid substrate experiments for state 3, 4, and uncoupled (p<0.05 for all), aligning with our previous reports in aorta. These data support a model wherein altered PVAT phenotype and FA composition impacts lipid transport and utilization. These changes are associated with differential impact on vascular impairment between females and males. These results provide insights into sex differences in PVAT contributions to vascular disease progression and vascular crosstalk. Disclosure A.C.Keller: None. M.M.Henckel: None. L.Knaub: None. G.Pott: None. G.James: None. L.A.Walker: None. J.E.B.Reusch: Advisory Panel; Medtronic. Funding National Center for Research Resources (UL1RR025780); U.S. Department of Veterans Affairs (BX002046 to J.E.B.R.), (BX003185 to A.C.K.); National Institutes of Health (R01 DK124344-01A1 to J.E.B.R.); Denver Research Institute; Ludeman Family Center for Women’s Health Research at the University of Colorado Anschutz Medical Campus; Junior Faculty Research Development Grant (to A.C.K.)