Fibroblast growth factor 21 levels in young healthy females display day and night variations and are increased in response to short-term energy deprivation through a leptin-independent pathway

Abstract

Objective: Fibroblast growth factor (FGF)-21 is an endocrine factor with potent metabolic effects. Its day-night patterns of secretion and/or its physiological response to energy deprivation and relationship to free fatty acids (FFAs) and/or leptin remain to be fully elucidated. We aim to elucidate day-night pattern of FGF-21 levels and its relationship to FFA, to assess whether energy deprivation alters its circulating patterns, and to examine whether leptin may mediate these changes.

Research design and methods: Six healthy lean females were studied for 72 h in a cross-over interventional study under three different conditions: on isocaloric diet and in a fasting state with administration of either placebo or metreleptin in physiological replacement doses. Blood samples were obtained hourly from 8:00 a.m. on day 4 until 8:00 a.m. on day 5.

Results: FGF-21 exhibited day-night variation pattern during the isocaloric fed state. Fasting significantly increased FGF-21 levels (P < 0.01) via a leptin-independent pathway. Day-night variation pattern in the fed state was lost on fasting. Leptin replacement in the hypoleptinemic state restored approximate entropy of FGF-21 time series but did not alter circulating levels. FGF-21 levels were closely cross-correlated with FFA levels in all three states.

Conclusions: A day-night variation in the levels of FGF-21 exists in young lean females in the fed state. Energy deprivation increases FGF-21 levels via a leptin-independent pathway. The interaction between FGF-21 and starvation-induced lipolysis, as indicated by its close cross-correlations with FFA in both fed state and energy deprivation, needs to be studied further.

Trial registration: ClinicalTrials.gov NCT00140231.

Figure 1

A: Day–night variation of mean FGF-21 levels (pg/mL) in the fed state. Adjusted coefficient of determination (R²) is displayed at the top center. Solid line represents 95% confidence interval and interrupted line represents 95% prediction interval (n = 6). B: Day–night variation of mean FFA (mEq/L) levels in the fed state. Adjusted coefficient of determination (R²) is displayed at the top center. Solid line represents 95% confidence interval and interrupted line represents 95% prediction interval (n = 6). (A high-quality color representation of this figure is available in the online issue.)

Figure 2

A: FGF-21 AUC in all three states demonstrating increase in levels in response to fasting; similar letters signify no statistical significant difference at the 0.05 level (n = 6). B: ApEn (m = 1, tolerance = 0.2, ApEn [1, 0.2]) of FGF-21 in all three states; similar letters signify no statistical significant difference at the 0.05 level (n = 6). C: Relationship between change of the AUC of FGF-21 between fed state and fasting state and FFA (mEq/L) levels before and after 72-h fast. Each point represents a single subject. Interrupted line represents 95% confidence interval (n = 6). (A high-quality color representation of this figure is available in the online issue.)

Figure 3

A: Mean FGF-21 and FFA for all six subjects in the fed state. Solid lines represent FGF-21 levels and interrupted lines represent FFA levels (n = 6). B: Mean FGF-21 and FFA for all six subjects in the fasting with placebo state. Solid lines represent FGF-21 levels and interrupted lines represent FFA levels (n = 6). C: Mean FGF-21 and FFA for all six subjects in the fasting with leptin replacement state. Solid lines represent FGF-21 levels and interrupted lines represent FFA levels (n = 6). (A high-quality color representation of this figure is available in the online issue.)