Endothelial ULK1 Regulates High-Fat Diet–Induced Obesity via FGF-21

Fibroblast grow factor (FGF) 21 is a hormone with huge potential for pharmaceutical development for treatment of metabolic disease. The role of endothelial cell (EC)-derived FGF-21 in obesity remains largely unknown, although we detected lower EC-FGF-21 levels in visceral fat of Ob/Ob and high-fat diet (HFD)-fed mice than the control lean mice. This study was to identify the role and mechanism of EC-FGF-21 in HFD-induced obesity using cell culture and mouse models. Mimicking HFD, long-term incubation with palmitate (100 µM, 16h) reduced FGF-21 levels in HUVEC that were co-cultured with 3T3-L1-adipocytes. The reduction was prevented in ULK1-siRNA-treated HUVEC, via ATF4-promoted mRNA expression and increased protein stability of FGF-21. Thus, FGF-21-induced expression of FGF-R1c, β-Klotho, UCP1 and GLUT1 was enhanced in co-cultured adipocytes. To confirm these findings in vivo, we used a Tie2/Cre-lox system to generate mice with EC-knockout of FGF-21 (FKO), ULK1 (UKO), or both (DKO). In 8-to-10-week-old male mice (n=15-20/group) fed an HFD (TestDiet: 60% energy from fat) for 3 months, wild type (WT, C57BL/6J) mice developed obesity and insulin resistance, which was worsened in FKO mice. In contrast, UKO mice gained less body weight and visceral fat mass and had improved glucose tolerance, without significant differences in food and water intake. Levels of adipose EC-FGF-21 was normalized in UKO mice, as determined by immunohistochemistry of FGF-21 and EC markers (CD31 and lectin). Expression of adipose FGF-R1c, β-Klotho, UCP1, and GLUT1 was restored in UKO, but not WT, mice. Concomitant with UCP1 induction, the visceral fat showed beige-cell-like deposits with fewer expanded adipocytes. However, this favorable phenotype was absent in DKO mice.

In summary, EC-ULK1 mediated HFD-induced obesity and insulin resistance through loss of EC-FGF-21, at least in part, by blunting local FGF-21-signaling in adipose tissue. Therapeutic targeting of the EC-ULK1-FGF-21 pathway may be a new treatment for obesity and insulin resistance.