FGF21, a member of the FGF19 subfamily, functions as an endocrine hormone to regulate glucose, lipid, and energy metabolism. FGF21 activates a unique dual receptor complex: bKlotho and FGF receptor tyrosine kinase. Since FGF21 relies on βKlotho as a co-receptor, FGF21 activity is restricted to those metabolic target tissues that express βKlotho. When administered acutely, FGF21 reduces blood glucose and insulin levels in ob/ob mice. Three hours after a single FGF21 injection, fasting blood glucose is decreased and glucose clearance is improved during GTT in DIO mice. Chronic treatment with FGF21 dose-dependently reduces body weight, fasting blood glucose, insulin, and lipid  levels  in  DIO  mice.  Obese cynomolgous  monkeys  treated  with  FGF21  for  4  weeks  show decreases in body weight, insulin, and triglyceride levels. No significant adverse effects on bone mineral density were identified in DIO mice treated with FGF21 for 2 weeks. FGF21 KO mice and WT mice fed a high fat diet and treated with PPAR a or g agonists showed similar responses on body weights, glucose and lipid levels, and tissue weights.  This result suggests a lack of or very minimal cross-talk between PPAR a or g agonists and the FGF21 pathway.

Multiple approaches were employed to develop therapies to target the FGF21 pathway. Agents tested that retained or mimicked the activities of FGF21 included a fusion protein consisting of Fc fused to FGF21 and agonistic antibodies that bind βKlotho and FGFR1c. Weekly or biweekly administration of these agents decreased body weight, insulin, and triglyceride levels in obese normoglycemic monkeys.

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