Several recent studies using direct ablation of FGFR1 or KLB in adipocytes, administration of activating antibody targeting specifically the FGFR1-KLB complex, or induction of dysfunctional adipose tissue (40–44) provide compelling evidence that adipose tissue and adipocyte FGFR1-KLB is the primary tissue and molecular target of inter-organ messenger FGF21, respectively. Although many types of tissues and cells express FGFR1 alone, mature adipocytes co-express FGFR1 with KLB, the transmembrane co-receptor for FGF21 and FGF19 (45). Similar to the general ablation of FGF21 (8), adipocyte-specific FGFR1 ablation resulted in few overt changes in adipogenesis, adipose secretory function, and systemic metabolic status under normal physiological conditions (46). However, under the metabolic stress of starvation, the absence of adipocyte FGFR1 caused increased adipocyte lipolysis. This occurred concurrently with elevation of serum triglycerides and fatty acids while indirectly causing an increase in hepatic lipogenesis and steatosis (46). This indicated that under such conditions adipocyte FGFR1 signaling dampens adipocyte lipolysis while concurrently dampening hepatic steatosis. Paradoxically yet most dramatically, the adipocyte FGFR1 deficiency abrogated nearly all the anti-obese and anti-diabetic effects elicited by pharmacological levels of FGF21
