Figure 1. FGF21 gets detailed. Researchers from Amgen Inc. and Roche's Genentech Inc. unit have separately published studies that suggest using antibodies to mimic fibroblast growth factor 21 (FGF21) action could help treat metabolic diseases, including type 2 diabetes and obesity.

In addition, separate teams at Eli Lilly and Co., Harvard Medical School and The University of Texas Southwestern Medical Center have elucidated downstream cellular functions that help explain how FGF21 exerts its antidiabetic effects.

In adipose tissue, FGF21 binds to and activates an FGF receptor 1c isoform (FGFR1c) and klotho-b (KLB) complex [a]. This triggers a signaling cascade that leads to activation of peroxisome
proliferation-activated receptor-
g (PPARG; PPARg) and PPARG coactivator 1a (PPARGC1A; PGC-1a) [b]. These transcriptional regulators then act to upregulate downstream targets that trigger uptake of glucose, browning of white adipose tissue, induction of thermogenesis and increases in oxidative metabolism [c].

In obese monkeys, an Amgen antibody designed to specifically activate the FGFR1c and KLB complex mimicked the antidiabetic actions of FGF21. In mice, adipocyte-specific deletion of Fgfr1c blocked the blood glucose-lowering effects of Fgf21 compared with no deletion. Together, these results suggest that targeting the FGFR1c and KLB complex in adipocytes is primarily responsible for the therapeutic action of FGF21.