FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk

Abstract

The liver regulates energy partitioning and utilization 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 utilization to reduce hepatic lipid storage. Here we report that FGF21 alters hepatic transcriptional and metabolic responses, and reduces 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 à cAMP à EPAC1 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.

Fibroblast growth factor-21 induces skeletal muscle atrophy and increases plasma amino acids in female mice: a potential role for glucocorticoids

“…These included: 'Folate metabolism', 'Catecholamine biosynthesis', 'Thyroid hormone synthesis', 'Tyrosine metabolism', and 'Arachidonic acid metabolism'. In agreement with our recent report that the effect of FGF21 to reduce hepatic and adipose tissue triglycerides is more apparent in male mice compared to female littermates (38), the top-five most enriched pathways in males were related to lipid metabolism (Fig. 2A).…”

“…Recent work by ourselves and others revealed that the benefit of FGF21 for hepatic lipid metabolism is sex dependent. FGF21 decreased liver triglycerides in obese male mice, but this was abrogated among obese female littermates (38,39). Thus, sex is an important biological variable influencing FGF21 physiology.…”

“…Plasma was submitted to the West Coast Metabolomics Center at the University of California, Davis for untargeted primary metabolite analysis by automated liner exchange cold injection system (ALEX-CIS) gas chromatography time of flight (GCTOF) mass spectroscopy (MS). Data were acquired as previously described (38,52). Metabolomics data were analyzed using…”

Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21

“…The reduction in body weight of males was attributed to decreased fat mass, as was true for our study. Interestingly, in their study food intake was also increased in female and not male mice upon FGF21 treatment, which was fully reversed in ovariectomized and aged female mice 47 . These results strongly suggest that the effects of FGF21 administration to decrease body weight are counteracted by ovarian/sex hormones and this leads to increased food intake, as we observed as well.…”

“…For instance, in A y mice, females were resistant to weight loss and their food intake was increased upon FGF21 treatment, which was in stark contrast with the effects in males 46 . Later, Chaffin et al showed that administration of FGF21 triggers body weight loss in male C57BL/6J, but not female mice, even though circulating FGF21 levels in plasma were similar between sexes 47 . The reduction in body weight of males was attributed to decreased fat mass, as was true for our study.…”