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Fibroblast growth factor 21 (FGF21) is a stress hormone that is released from the liver in response to nutritional and metabolic challenges. In addition to its well-described effects on systemic metabolism, a growing body of literature now supports the notion that FGF21 also acts via the central nervous system to control feeding behavior. Here we review the current understanding of FGF21 as a hormone regulating feeding behavior in rodents, non-human primates, and humans. First, we examine the nutritional contexts that induce FGF21 secretion. Initial reports describing FGF21 as a ‘starvation hormone’ have now been further refined. FGF21 is now better understood as an endocrine mediator of the intracellular stress response to various nutritional manipulations, including excess sugars and alcohol, caloric deficits, a ketogenic diet, and amino acid restriction. We discuss FGF21’s effects on energy intake and macronutrient choice, together with our current understanding of the underlying neural mechanisms. We argue that the behavioral effects of FGF21 function primarily to maintain systemic macronutrient homeostasis, and in particular to maintain an adequate supply of protein and amino acids for use by the cells.

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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.

Neuroendocrine circuits underlying stress integration and systemic fuel homeostasis are substantially intertwined. Accordingly, metabolic diseases such as obesity and diabetes have a high incidence of co-morbidity with stress-associated psychological disorders like anxiety and depression. Importantly, there is a strong female bias in both metabolic and stress-related disorders, making the understanding of sex-specific functions of these pathways critical for treatment. The hypothalamic melanocortin system is a principal regulator of energy balance and also modulates HPA responses to acute stress. Mutations in the melanocortin-4 receptor (MC4R) is the most common monogenic cause of obesity in humans and has been associated with sex-dependent effects, such as more women than men exhibiting ‘emotional’ eating, a behavior that is thought to be stress-induced. Thus, we hypothesized that MC4R deficiency may cause sexually dimorphic metabolic and stress responses. We subjected male and female rats with a MC4R loss-of-function mutation to either chronic variable stress (CVS) or no stress for 31 days. Mid-study, all rats underwent an acute restraint stress challenge. Consistent with previous reports, male and female rats with MC4R deficiency had increased food intake and body weight, which were both decreased by CVS. Contrary to expectation, MC4R genotype did not affect HPA axis or metabolic responses to chronic stress. But importantly, we observed a significant interaction between MC4R genotype and sex in HPA axis tone and acute stress reactivity, such that MC4R deficiency blunted both endpoints in males but exaggerated them in females. Females showed a dramatic 259% and 419% increase in basal corticosterone and HPA reactivity, respectively, compared to males. The heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. Disclosure A.T.B. Chaffin: None. Y. Fang: None. K.R. Larson: None. J. Mul: None. K.K. Ryan: None. Funding National Institutes of Health (R00HL111319)