Dipeptidyl peptidase IV inhibitor lowers PPARγ agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention

Peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists like pioglitazone (PGZ) are effective antidiabetic drugs, but they induce fluid retention and body weight (BW) gain. Dipeptidyl peptidase IV (DPP IV) inhibitors are antidiabetic drugs that enhance renal Na+ and fluid excretion. Therefore, we examined whether the DPP IV inhibitor alogliptin (ALG) ameliorates PGZ-induced BW gain. Male Sv129 mice were treated with vehicle (repelleted diet), PGZ (220 mg/kg diet), ALG (300 mg/kg diet), or a combination of PGZ and ALG (PGZ + ALG) for 14 days. PGZ + ALG prevented the increase in BW observed with PGZ but did not attenuate the increase in body fluid content determined by bioimpedance spectroscopy (BIS). BIS revealed 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. Conversely, PGZ but not ALG increased mRNA expression of thermogenesis mediator uncoupling protein 1 in epididymal WAT. Adding ALG to PGZ treatment increased the abundance of multilocular cell islets in sc WAT, and PGZ + ALG increased the expression of brown-fat-like beige cell marker TMEM26 in sc WAT and interscapular brown adipose tissue and increased rectal temperature vs. vehicle. In summary, DPP IV inhibition did not attenuate PPAR gamma agonist-induced fluid retention but prevented BW gain by reducing FM. This involved ALG inhibition of food intake and was associated with food intake-independent synergistic effects of PPAR gamma agonism and DPP-IV inhibition on beige/brown fat cells and thermogenesis.