Head Over Hepatocytes for FGF21

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is critical for regulation of intermediary metabolism, and it is also a potential drug target for treating diabetes and other metabolic diseases. Interest in FGF21 exploded with the discovery that pharmacological administration of FGF21 to diabetic rodents and primates increased insulin sensitivity, energy expenditure, and weight loss (1). Administration of the FGF21 analog, LY2405319, to obese humans also significantly reduced body weight and improved plasma metabolic profiles (2). These studies have spurred a number of drug development programs designed to enhance FGF21 activity as a therapeutic approach to increase insulin sensitivity and treat diabetes.FGF21 is expressed in and secreted by several tissues including liver, white adipose tissue, brown adipose tissue, striated muscle, heart, and pancreas. However, recent work has demonstrated that plasma FGF21 levels are derived primarily, if not completely, from the liver (3). FGF21 signals to specific tissues that express both the traditional FGF receptor, FGFR1, and a coreceptor called βKlotho. The physiological importance of FGF21 in regulating adaptive metabolic responses was demonstrated when complimentary articles showed that FGF21 was highly induced in liver by fasting through activation of the peroxisome proliferator–activated receptor α (4,5). Using multiple gain-of-function models, Inagaki et al. (4) showed that FGF21 produced by the liver acts as an endocrine hormone to coordinate adipose tissue lipolysis and stimulate ketogenesis, both critical responses to …