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FGF21 and the late adaptive response to starvation in humans
Pouneh K. Fazeli, … , Parth Patwari, Matthew L. Steinhauser
Pouneh K. Fazeli, … , Parth Patwari, Matthew L. Steinhauser
Published November 3, 2015
Citation Information: J Clin Invest. 2015;125(12):4601-4611. https://doi.org/10.1172/JCI83349.
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Research Article Endocrinology

FGF21 and the late adaptive response to starvation in humans

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Abstract

In mice, FGF21 is rapidly induced by fasting, mediates critical aspects of the adaptive starvation response, and displays a number of positive metabolic properties when administered pharmacologically. In humans, however, fasting does not consistently increase FGF21, suggesting a possible evolutionary divergence in FGF21 function. Moreover, many key aspects of FGF21 function in mice have been identified in the context of transgenic overexpression or administration of supraphysiologic doses, rather than in a physiologic setting. Here, we explored the dynamics and function of FGF21 in human volunteers during a 10-day fast. Unlike mice, which show an increase in circulating FGF21 after only 6 hours, human subjects did not have a notable surge in FGF21 until 7 to 10 days of fasting. Moreover, we determined that FGF21 induction was associated with decreased thermogenesis and adiponectin, an observation that directly contrasts with previous reports based on supraphysiologic dosing. Additionally, FGF21 levels increased after ketone induction, demonstrating that endogenous FGF21 does not drive starvation-mediated ketogenesis in humans. Instead, a longitudinal analysis of biologically relevant variables identified serum transaminases — markers of tissue breakdown — as predictors of FGF21. These data establish FGF21 as a fasting-induced hormone in humans and indicate that FGF21 contributes to the late stages of adaptive starvation, when it may regulate the utilization of fuel derived from tissue breakdown.

Authors

Pouneh K. Fazeli, Mingyue Lun, Soo M. Kim, Miriam A. Bredella, Spenser Wright, Yang Zhang, Hang Lee, Ciprian Catana, Anne Klibanski, Parth Patwari, Matthew L. Steinhauser

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Figure 2

Human fasting is associated with downregulation of thermogenic activity in adipose tissue.

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Human fasting is associated with downregulation of thermogenic activity ...
(A) FDG-PET/MRI images of a representative subject before and after the 10-day fast. In coronal FDG-PET images (top row), arrows indicate FDG uptake in the cervical and supraclavicular regions at baseline, which disappeared with fasting. T1-weighted MRI images (middle row) and fused FDG-PET/MRI images (bottom row) localized FDG uptake to adipose tissue, consistent with BAT. Of the 5 subjects with detectable BAT at baseline, none had significant areas of FDG avidity after 10 days of fasting. P < 0.05, binomial test. (B) qPCR performed on human periumbilical sWAT samples collected at baseline and on days 1 and 10 of fasting showed fasting-mediated downregulation of transcriptional regulators of the thermogenic program. Data are expressed as the mean ± SEM and were analyzed by repeated-measures ANOVA and Dunnett’s test for multiple comparisons (n = 7). Note: UCP1 was measured but not detectable; PRDM16 data represent a subset of 5 subjects with detectable transcript levels. *P < 0.05, **P < 0.01. (C) Resting energy expenditure measured by indirect calorimetry. Note that the y axis starts at 800 kcal/d. (D) Serial circulating adiponectin during human fasting. Data are normalized to baseline values and displayed as Tukey box plots. P < 0.01, paired t test. Mean baseline adiponectin level: 9.9 μg/ml ± 5.7 (SD). Note that the y axis starts at 50%. (E) Serial circulating total T3 levels during human fasting. Data are normalized to baseline values and displayed as a Tukey box plot. P < 0.01, baseline level compared with day 10 using a Wilcoxon signed-rank test. Median baseline T3 level with interquartile range: 116.6 ng/dl (99.3, 129.7). Note that the y axis starts at 50%. (F) qPCR performed on the samples analyzed in B demonstrate fasting-mediated downregulation of thyroid effector genes in human sWAT. Repeated-measures ANOVA and Dunnett’s test for multiple comparisons were used to analyze the data, which are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.005.
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