Diabetes. 2025 Jan 09. pii: db240289. [Epub ahead of print]
To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion. Furthermore, to assess the role of adipose tissue thermogenesis in protecting against overfeeding-induced weight gain, we analyze the expression of genes involved in futile metabolic cycles in response to overfeeding and subject uncoupling protein 1 (UCP1) knockout (KO) mice to intragastric overfeeding. Data from two independent experiments demonstrate that 7 days of 140-150% overfeeding results in substantial weight gain and triggers a potent, sustained decrease in voluntary food intake, which coincides with a gradual return of body weight toward baseline after overfeeding. Intragastric overfeeding triggers an increase in energy expenditure that seems to be adaptive. However, mice lacking UCP1 are not impaired in their ability to defend against overfeeding-induced weight gain. Finally, we show that fecal energy excretion decreases in response to overfeeding, but only during the recovery period, driven primarily by a reduction in fecal output rather than in fecal caloric density. In conclusion, while overfeeding may induce adaptive thermogenesis, the primary protective response to forced weight gain in mice appears to be a potent reduction in food intake.