Sex differences in the effects of brown adipocyte CD47 deficiency on age-related weight change and glucose homeostasis

Our previous studies demonstrated that mice with global CD47 deficiency are lean and resistant to diet or aging-associated obesity and metabolic complications. This protective effect is partially through modulating brown fat function. To definitively determine the role of brown fat CD47 in age-related metabolic homeostasis, inducible brown adipocyte-specific cd47 deficient mice were generated by crossbreeding cd47 floxed mice with UCP1-CreERT2 mice and characterized in this study. Efficient knockdown of CD47 in brown fat was achieved in both male and female mice through tamoxifen administration. Intriguingly, our findings indicated that male mice lacking CD47 in brown fat displayed a notable reduction in body weight starting at 23 weeks of age when housed at a temperature of 22 °C, in comparison to control mice. This reduction in weight was accompanied by improved glucose tolerance. Remarkably, this phenotype persisted even when the male mice were housed under thermoneutral conditions (30 °C). Conversely, female knockout mice did not exhibit significant changes in weight throughout the study. In addition to the enhanced glucose homeostasis, brown fat CD47 deficiency in male mice also prevented age-related hypertriglyceridemia and non-alcoholic fatty liver disease. Furthermore, the brown fat tissue of male knockout mice exhibited reduced whitening, along with increased expression of Glut 4 and FGF21, suggesting the involvement of a thermogenesis-independent mechanism. Altogether, these findings highlight a sex difference in the impact of brown adipocyte CD47 deficiency on age-related weight changes and glucose homeostasis.