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FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk
Aki T. Chaffin, … , Michael L. Goodson, Karen K. Ryan
Aki T. Chaffin, … , Michael L. Goodson, Karen K. Ryan
Published August 23, 2022
Citation Information: JCI Insight. 2022;7(19):e155848. https://doi.org/10.1172/jci.insight.155848.
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Research Article Endocrinology Hepatology

FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk

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Abstract

The liver regulates energy partitioning and use in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor 21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate use to reduce hepatic lipid storage. Here we report that FGF21 altered hepatic transcriptional and metabolic responses, and reduced liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss–independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor → cAMP → exchange protein directly activated by cAMP signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

Authors

Aki T. Chaffin, Karlton R. Larson, Kuei-Pin Huang, Chih-Ting Wu, Nadejda Godoroja, Yanbin Fang, Devi Jayakrishnan, Karla A. Soto Sauza, Landon C. Sims, Niloufar Mohajerani, Michael L. Goodson, Karen K. Ryan

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Figure 4

FGF21 signaling in white adipose tissue is sex dependent.

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FGF21 signaling in white adipose tissue is sex dependent.
At 2 hours fol...
At 2 hours following its i.p. injection, recombinant human FGF21 (0.1 mg/kg) was elevated in plasma collected from DIO male and female mice (A). We observed no effect of FGF21 on the expression of immediate early gene Egr1 in liver (B). FGF21 increased Egr1 in BAT (C) and WAT (D) of both male and female DIO mice. In WAT, endogenous expression of Fgf21 was greater in males than females. Pharmacological injection of FGF21 reduced its endogenous expression, and this was more apparent among females (E). FGF21 treatment altered WAT Fgfr1 expression in a sex-dependent manner, such that FGF21 tended to increase Fgfr1 expression in males and decrease it in females (F). FGF21 decreased WAT Klb expression, and this effect was more apparent among females (G). Analyses made by 2-way ANOVA, Tukey post hoc test, **P < 0.01. Data are shown as mean ± SEM; n = 8–9 mice/group.

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ISSN 2379-3708

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