Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

Abstract

BACKGROUND Fibroblast growth factor (FGF) 21 is an endocrine factor actively involved in glucose and lipid metabolism in rodents. However, little is known about its physiological function and regulation in humans. This study investigated the diurnal changes in circulating FGF21 concentrations and their association with other metabolic markers in both obese and lean individuals. METHODS A total of 36 volunteers were assigned to 2 groups. One group received 3 standardized meals and another group was fasted for 24 h. Blood samples were drawn every 30 min throughout a 24-h period. Circulating FGF21 concentrations were measured with an in-house chemiluminescence immunoassay. The effects of fatty acids on hepatic production of FGF21 were determined by using real-time PCR. RESULTS In both the fasting and standardized meals groups, circulating FGF21 began to rise at midnight, reaching a peak in the early morning and then declining to basal concentrations early in the afternoon. Baseline concentrations of circulating FGF21 were much higher in obese individuals than in lean individuals (P < 0.05). However, the magnitude of the nocturnal rise in circulating FGF21 was significantly blunted in obese individuals. The 24-h oscillatory pattern of circulating FGF21 resembled that of free fatty acids and cortisol, but was opposite to the patterns of insulin and glucose. Unsaturated fatty acids induced time-dependent expression of FGF21 mRNA in human hepatocytes. CONCLUSIONS These findings support the role of FGF21 as an important metabolic regulator that integrates the circadian rhythm with energy homeostasis in humans. Diurnal rhythms of circulating FGF21 could be partly caused by the oscillation of free fatty acids.