FGF21 regulates ceramide levels preferentially in visceral vs. subcutaneous white adipose tissue in aged mice fed a high-fat diet

Fibroblast growth factor-21 (FGF21) is a hormone that promotes energy balance, insulin sensitivity, and longevity. FGF21 reduces ceramide levels, bioactive sphingolipids that accumulate and contribute to adipose tissue inflammation and dysfunction that underlies cardiometabolic disease and diseases associated with aging. Specific ceramides are linked to disease, however, how FGF21 alters specific ceramide species in adipose tissue has not been investigated. We generated mice with doxycycline-inducible, adipocyte-specific overexpression of FGF21 and fed them a HFD for 1.5 years. LC–MS/MS analysis was performed for adipose tissue sphingolipids. In visceral epididymal (eWAT), ceramide species (C16, C18, C20, C22, and C24:1) were significantly decreased in transgenic vs. control mice. In contrast, in subcutaneous adipose tissue (scWAT), ceramides C24 and C25 increased in transgenic mice. Furthermore, six species of hexosyl- and lactosyl-ceramides species were reduced in eWAT in transgenic vs control mice. Upon FGF21 overexpression, lipids generated from the breakdown of ceramide, sphinganine, and sphingosine, were significantly lowered in eWAT, but were not altered in scWAT. Overexpression of FGF21 in adipocytes robustly increases serum adiponectin levels, which is anti-inflammatory in part because adiponectin receptors possess intrinsic ceramidase activity, thereby breaking down ceramides. By crossing mice with adipocyte-specific FGF21 overexpression with adiponectin KO mice, we observed that FGF21 lowers ceramides in eWAT in the absence of adiponectin. In contrast, FGF21 alterations of scWAT ceramide levels depend on the presence of adiponectin. This suggests that FGF21 signaling and crosstalk with adiponectin to lower ceramides in eWAT and scWAT differ. Our findings hold important implications for understanding the role of FGF21 in adipose tissue across lifespan. The reduction in ceramides was most pronounced in eWAT, which may mediate the anti-inflammatory effects of FGF21. Additionally, these results are relevant to the discovery of the mechanisms by which FGF21 increases longevity, since we recently have shown that FGF21 does not increase energy expenditure in aged mice. This indicates that FGF21 ceramide lowering activity in peripheral tissues may prevent metabolic disease especially later in life. In essence, our research has unveiled a novel aspect of FGF21 function, shedding light on its differential impact on inflammation and insulin sensitivity in visceral vs subcutaneous adipose tissue. K01DK131252 to CMG; 5P01AG051459-08 to VD and PES This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.