Circulating FGF21 is induced by PPAR agonists but not ketosis in Man. Christodoulides C, Dyson P, Sprecher D, Tsintzas K, Karpe F. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK; NIHR Oxford Biomedical Research Centre, ORH Trust, Churchill Hospital, Oxford, UK; Cardiovascular and Urogenital Centre for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania; Centre for Integrated Systems Biology and Medicine, School of Biomedical Sciences, Nottingham University, Nottingham, NG7 2UH, United Kingdom.
CONTEXT: Murine fibroblast growth factor (FGF) 21 is a nutritionally regulated hormone secreted by the liver principally in response to peroxisome proliferator-activated receptor-alpha (PPARalpha) activation, which plays a critical role in regulating metabolism during ketosis. FGF21 is also a PPARgamma target gene in mouse adipose tissue. Little information is available on FGF21 functions in humans. OBJECTIVE: To measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans. DESIGN: Prospective study involving 3 patient groups. SETTING: Two university hospitals. PATIENTS: Eight healthy male volunteers undergoing a 48-hour period of starvation followed by 24-hours re-feeding (group 1); Seven obese individuals allocated to a low-carbohydrate diet for 3 months (group 2); Three groups of healthy, overweight or obese male volunteers receiving treatment with a PPARalpha (20 microg/day GW590735) (n=6), PPARdelta (10 mg/day GW501516) (n=6), or PPARgamma agonist (rosiglitazone) (n=10) for 2 weeks (group 3). MAIN OUTCOME MEASURES: Fasting plasma FGF21 and serum 3-hydroxybutyrate. RESULTS: There was no significant variation in human plasma FGF21 during fasting and re-feeding. A three month ketogenic diet was associated with a 42% decline in plasma FGF21 levels. Circulating FGF21 increased significantly in response to treatment with PPARalpha (39%) and PPARdelta (32%) but not PPARgamma agonists. CONCLUSION: FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPARalpha and PPARdelta and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.
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