Pioglitazone-Enhanced Brown Fat Whitening Contributes to Weight Gain in Diet-Induced Obese Mice

Pioglitazone is an insulin sensitizer used for the treatment of type 2 diabetes mellitus (T2DM) by activating peroxisome proliferator-activated receptor gamma. This study aimed to investigate the effects of pioglitazone on white adipose tissue (WAT) and brown adipose tissue (BAT) in diet-induced obese (DIO) mice.

C57BL/6 mice were treated with pioglitazone (30 mg/kg/day) for 4 weeks after a 16-week high-fat diet (HFD) challenge. Body weight gain, body fat mass, energy intake, and glucose homeostasis were measured during or after the treatment. Histopathology was observed by hematoxylin and eosin, oil red O, immunohistochemistry, and immunofluorescence staining. Expression of thermogenic and mitochondrial biogenesis-related genes was detected by quantitative real-time PCR and western blotting.

After 4-week pioglitazone treatment, the fasting blood glucose levels, glucose tolerance, and insulin sensitivity were significantly improved, but the body weight gain and fat mass were increased in DIO mice. Compared with the HFD group, pioglitazone did not significantly affect the weights of liver and WAT in both subcutaneous and epididymal regions. Unexpectedly, the weight of BAT was increased after pioglitazone treatment. Histological staining revealed that pioglitazone ameliorated hepatic steatosis, reduced the adipocyte size in WAT, but increased the adipocyte size in BAT.

Though pioglitazone can promote lipolysis, thermogenesis, and mitochondrial function in WAT, it leads to impaired thermogenesis, and mitochondrial dysfunction in BAT. In conclusion, pioglitazone could promote the browning of WAT but led to the whitening of BAT; the latter might be a new potential mechanism of pioglitazone-induced weight gain during T2DM treatment.