LAUSR

Obesity was recognized as a disease only in 1998. Currently, obesity has reached epidemic levels affecting half of the US population. Obesity, which is characterized by increased body mass index (BMI), body fat distribution and adipose tissue dysfunction, often contributes to overall metabolic dysregulation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipose tissue and plays a role in glucose and lipid metabolism. PPARγ function can be regulated by acetylation. Our lab has found that PPARγ deacetylation exerts a vasculo-protective role. Whether PPARγ deacetylation protects against obesity-related metabolic dysregulation requires further investigation. We hypothesized that PPARγ deacetylation prevents obesity-induced glucose and lipid dysregulation in male mice. Eight-week-old male mice constitutively deacetylated for PPARγ containing a lysine to arginine knock-in mutation (K268R/K293R; 2KR mice) and C57BL/6 mice were randomized into two experimental groups. Control Groups (n=8 C57BL/6; n=5 2KR) were fed a standard chow diet (5% fat and 58.7% carbohydrate [3.2% sucrose]) and Western Diet (WD) Groups (n=12 C57BL/6; n=5 2KR) received a WD (21% fat and 50% carbohydrates [34% sucrose]) for 16 weeks. The WD-fed C57BL/6 and 2KR mice developed obesity as confirmed by increased body weight (39.88 ± 1.78 g vs. 29.41 ± 0.54 g C57BL/6 controls; 33.80 ± 1.42 g vs 24.76 ± 0.55 g 2KR controls, p<0.05), BMI (4.15 ± 0.15 kg/m2 vs 3.91 ± 0.20 kg/m2 C57BL/6 controls; 3.68 ± 0.12 kg/m2 vs 2.92 ± 0.06 kg/m2 2KR controls, p<0.05) and waist circumference (9.50 ± 0.27 cm vs 8.38 ± 0.13 cm C57BL/6 controls; 9.10 ± 0.29 cm vs 7.40 ± 0.10 cm 2KR controls, p<0.05) in both cohorts. As expected, obese C57BL/6 mice exhibited glucose intolerance as per glucose tolerance testing (42908.14 ± 1720.90 a.u. vs 32732.83 ± 2386.96 a.u. controls, p<0.05), elevated fasting blood glucose levels (152.67 ± 3.88 mg/dL vs 138.63 ± 3.44 mg/dL controls, p<0.05), and elevated cholesterol levels (174.05 ± 37.33 mg/dL vs 32.75 ± 4.64 mg/dL controls, p<0.05). Strikingly, 2KR obese male mice did not exhibit significant changes in fasting blood glucose level (125.60 ± 11.54 mg/dL vs 98.40 ± 4.02 mg/dL 2KR controls, p=0.057), but showed elevated cholesterol levels (126.9 ± 14.15 mg/dL vs 55.46 ± 4.10 mg/dL 2KR controls, p<0.05). Interestingly, 2KR obese female mice (n=8) showed protection against hypercholesterolemia (79.37 ± 17.27 mg/dL vs 49.53 ± 2.88 mg/dL controls, p=0.064), indicating a sex difference. Histological analysis of midscapular brown adipose tissue (BAT) from obese C57BL/6 mice exhibited marked larger unilocular lipid droplets in brown adipocytes, while obese 2KR mice maintained the native BAT phenotype. Together, our results show that PPARγ deacetylation in males protects against metabolic dysregulation and BAT phenotypic changes caused by obesity despite weight gain. Diabetes Action Grant to Maria Alicia Carrillo-Sepulveda 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.