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FGF21 has been shown to normalize glucose, lipid, and energy homeostasis, and attracted considerable interest as a novel therapy for type 2 diabetes and obesity.It belongs to a distinctive subfamily of the fibroblast growth factors proteins (FGF19 subfamily) that can circulate in the blood stream and act as endocrine hormones.FGF21 requires the presence of bKlotho, a single-pass transmembrane protein, as the co-receptor to activate downstream signaling.Here we describe novel molecules we identified that will target FGF21 pathway in the similar bKlotho dependent fashion.Furthermore, we also demonstrated that those molecules are able to exert the same metabolic beneficial effect as FGF21.Such novel molecular entities may provide new opportunities to target FGF21 pathway for treatment of diabetes.