Brown Adipose Tissue-Derived GDF15 Mediates Energy Homeostasis in a Sex-Dependent Manner

Growth differentiation factor 15 (GDF15) is a distant member of the transforming growth factor-β (TGFβ) superfamily that can be expressed in several tissues. Studies have shown that in response to prolonged high-fat feeding and cold stress GDF15 can be induced in brown adipocytes. Importantly, administration of recombinant GDF15 in rodents and non-human primates (Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Sci. Transl. Med. 9, eaan8732 (2017) reduces food intake and body mass. Indeed, we have recently shown that in a model of mitochondrial stress, brown adipose tissue (BAT)-derived GDF15 is required to maintain energy homeostasis and cold-induced thermogenesis in mice. Nonetheless, the role of BAT-derived GDF15 during physiological stress is not known. In the present study, we tested the hypothesis that BAT-derived GDF15 is required to regulate cold-induced thermogenesis and energy homeostasis in high-fat fed mice. To test this hypothesis, we generated mice selectively lacking GDF15 in thermogenic adipocytes (brown and beige) (GDF15 BKO). GDF15 BKO male and female mice had normal body weight, body composition and glucose homeostasis under baseline conditions. In response to 4 hours of cold exposure following fasting, the decline in core body temperature in GDF15 BKO female mice was similar to that observed in their wild type (WT) counterparts. Conversely, GDF15 BKO male mice became hypothermic. Surprisingly, after 12 weeks on a high-fat diet (HFD), GDF15 BKO female mice weighed significantly less and had reduced fat mass relative to their WT controls, while male mice had increased body weight and fat accumulation. Furthermore, resistance to DIO in female mice was associated with increased energy expenditure, while food intake and locomotor activity were unchanged. When ovariectomized, GDF15 BKO females experienced similar weight gain and fat accumulation as WT mice and no longer had increased energy expenditure. Of note, estrogen receptor alpha ( Esr1) expression in BAT was significantly repressed in GDF15 BKO male mice fed high-fat diet but was maintained in female mice relative to their respective WT controls. Taken together, our data suggest that GDF15 expression in BAT is dispensable for thermoregulation in female mice but is required to regulate core body temperature in males. Furthermore, while GDF15 BKO male mice are susceptible, female mice are resistant to DIO via mechanisms likely involving sex hormones and increased resting metabolic rates. NIH DK125405 to R.O.P.; Diabetes Research Training Program funded by the NIH (T32 DK112751) to JJ and by the NIH 1R25GM116686 to L.M.G.P. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.