Dipeptidyl peptidase‐4 inhibitor lowers PPARγ agonist‐induced body weight gain by affecting food intake, fat mass and beige/brown fat but not fluid retention (1160.9)

Abstract

DPP‐4 inhibitors are anti‐diabetic drugs that enhance renal Na+ and fluid excretion. We tested whether the DPP‐4 inhibitor alogliptin (ALG) ameliorates PPARγ agonists pioglitazone (PGZ)‐induced fluid retention and body weight (BW) gain. Male Sv129 mice were treated with vehicle, PGZ (220mg/kg diet), ALG (300mg/kg diet) or PGZ+ALG for 14 days (n=8‐10/group). PGZ+ALG prevented the PGZ‐induced BW increase, but did not affect fluid retention as determined by bioimpedance spectroscopy (BIS). BIS showed that ALG alone had no effect on fat mass (FM), but enhanced the FM lowering effect of PGZ; MRI analysis confirmed the latter and showed reductions in visceral and inguinal subcutaneous (sc) white adipose tissue (WAT). ALG, but not PGZ, decreased food intake and plasma free fatty acid concentrations. PGZ, but not ALG, increased mRNA expression of thermogenesis mediator UCP1 in epididymal WAT. PGZ+ALG increased the expression of brown‐fat‐like “beige” cell marker TMEM26 in scWAT and interscapular brown adipose tissue and increased rectal temperature versus vehicle. All mentioned differences were statistically significant. In summary, DPP‐4 inhibition did not attenuate PPARγ agonist‐induced fluid retention, but prevented BW gain by reducing FM. This involved ALG‐inhibition of food intake and was associated with synergistic effects of PPARγ agonism and DPP‐4 inhibition on beige/brown fat cells and thermogenesis.