Going Back to the Biology of FGF21: New Insights

FGF21 is an endocrine factor shown to impact whole-body metabolism in preclinical species and adult humans. FGF21 is under investigation as a novel therapeutic agent for the treatment of diabetes and its associated comorbidities. Expression of the FGF21 receptor/β-klotho complex (FGFR1-KLB) determines target tissue specificity; adipose tissue, liver, and the central nervous system have emerged as key target organs. Engineered FGF21 analogs, at pharmacological levels, show considerable improvement in the metabolic syndrome phenotype in animal models. However, only some of these effects (reduced dyslipidemia and body weight) are evident in humans. This represents a significant challenge for the translational potential of engineered FGF21-based therapeutics. Fibroblast growth factor 21 (FGF21) is a protein highly synthesized in the liver that exerts paracrine and endocrine control of many aspects of energy homeostasis in multiple tissues. In preclinical models of obesity and type 2 diabetes, treatment with FGF21 improves glucose homeostasis and promotes weight loss, and, as a result, FGF21 has attracted considerable attention as a therapeutic agent for the treatment of metabolic syndrome in humans. An improved understanding of the biological role of FGF21 may help to explain why its therapeutic potential in humans has not been fully realized. This review will cover the complexities in FGF21 biology in rodents and humans, with emphasis on its role in protection from central and peripheral facets of obesity. Fibroblast growth factor 21 (FGF21) is a protein highly synthesized in the liver that exerts paracrine and endocrine control of many aspects of energy homeostasis in multiple tissues. In preclinical models of obesity and type 2 diabetes, treatment with FGF21 improves glucose homeostasis and promotes weight loss, and, as a result, FGF21 has attracted considerable attention as a therapeutic agent for the treatment of metabolic syndrome in humans. An improved understanding of the biological role of FGF21 may help to explain why its therapeutic potential in humans has not been fully realized. This review will cover the complexities in FGF21 biology in rodents and humans, with emphasis on its role in protection from central and peripheral facets of obesity.