Mitochondrial Akap1 Protein Is Required For Diet-induced Obesity, Glucose Dysregulation And Hypertension

Mitochondria are best known as the powerhouse of the cell playing a critical role in energy metabolism with important implications in the development of obesity, a major cause of type 2 diabetes and hypertension. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that promote protein kinase A (PKA)-mediated phosphorylation of Drp1(Ser637) by increasing the local concentration of PKA at the outer mitochondrial membrane. However, the role of AKAP1 in the regulation of body weight, glucose homeostasis and blood pressure is not known. We used AKAP1 deficient mice to understand the physiological significance of this protein. Male and female AKAP1 -/- and AKAP1 +/- mice fed normal chow exhibit normal body weight relative to littermate controls. In contrast, AKAP1 -/- and AKAP1 +/- mice fed high fat high/sucrose diet (HFHSD) display attenuated weight gain compared to controls (male: 39.5 + 1.7 and 42.5 + 1.6 vs 47.3 + 2.3g, and female: 29.7 + 1.3 and 29.2 + 1.8 vs 32.5 + 1.5g). This was associated with significant decreased in fat mass in AKAP1 -/- (male:16.2 + 0.9g and female: 8.7 + 1.1g) and AKAP1 +/- (male:15.0 + 2.5g and female: 9.2 + 1.0g) mice compared to controls (male: 21.2 + 1.7g and female: 13.9 + 1.6g) whereas lean mass was not different between the three groups. Glucose tolerance test revealed that female AKAP1 -/- mice have improved glucose handling, and insulin tolerance test showed that insulin sensitivity is better in male AKAP1 -/- mice than controls. Notably, blood pressure was significantly lower in HFHSD-fed male AKAP1 -/- (systolic: 124.4 + 6 mmHg) and AKAP1 +/- (116.4 + 3 mmHg) mice vs control mice (146.4 + 5 mmHg). These findings demonstrated the importance of AKAP1 in the development of obesity and associated diabetes and hypertension. Our data also point to mitochondria function as a potential therapeutic target for treatment of common obesity and related diseases.