Ryan, K. K. | Search bioRxiv

bioRxiv2023

The macronutrient content of a meal modulates subsequent 'dessert' intake, via Fibroblast Growth Factor 21 (FGF21)

Pharmacological administration of Fibroblast growth factor 21 (FGF21) alters food choice, including that it decreases the consumption of sucrose and other sweet tastants. Conversely, endogenous secretion of FGF21 by the liver is modulated by diet, such that plasma FGF21 is increased after eating foods that have a low dietary protein: total energy (P: E) ratio. Together, these findings suggest a strategy to promote healthy eating, in which the macronutrient content of a pre-load meal could reduce the later consumption of sweet desserts. Here, we tested the prediction that individuals eating a low P: E pre-load meal, and next offered a highly palatable sweet dessert, would eat less of the sugary snack compared to controls, due to increased FGF21 signaling. In addition to decreasing sweet intake, FGF21 increases the consumption of dietary protein. Thus, we predicted that individuals eating a low protein pre-load meal, and subsequently offered a very high-protein pellet as dessert or snack, would eat more of the high protein pellet compared to controls, and that this depends on FGF21. We tested this in C57Bl/6J, and liver-specific FGF21-null (FGF21{Delta}L) null male and female mice and littermate controls. Contrary to expectation, eating a low protein pre-load did not reduce the later consumption of a sweet solution in either males or females, despite robustly increasing plasma FGF21. Rather, eating the low protein pre-load increased later consumption of a high protein pellet. This was more apparent among males and was abrogated in the FGF21{Delta}L mice. We conclude that physiologic induction of hepatic FGF21 by a low protein pre-load is not sufficient to reduce later consumption of sweet dessert, though it effectively increases the subsequent intake of dietary protein in male mice.

physiology↗

bioRxiv2023

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

BackgroundFibroblast growth factor-21 (FGF21) is an intercellular signaling molecule secreted by metabolic organs, including skeletal muscle, in response to intracellular stress. FGF21 crosses the blood brain barrier and acts via the nervous system to coordinate aspects of the adaptive starvation response, including increased lipolysis, gluconeogenesis, hepatic fatty acid oxidation, and activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Given its beneficial effects for hepatic lipid metabolism, pharmaceutical FGF21 analogues are in clinical trials treatment of fatty liver disease. We predicted pharmacologic treatment with FGF21 in-creases HPA axis activity and skeletal muscle glucocorticoid signaling and induces skeletal muscle atrophy in mice. MethodsWe treated male and female mice with FGF21 or saline, delivered either pe-ripherally or directly to the brain, to determine its effect on skeletal muscle. To identify metabolic pathways affected by FGF21, we analyzed untargeted primary metabolites measured in plasma by GCTOF-MS. To determine mechanisms underlying sex-and FGF21-dependent changes in muscle mass, we measured hormonal and molecular mediators of muscle protein synthesis and degradation. We performed stable isotope labeling with deuterium oxide to directly measure muscle protein synthesis. ResultsA short course of systemic FGF21 treatment decreased muscle protein synthe-sis (P < 0.001) and reduced tibialis anterior weight (P < 0.05); this was driven primarily by its effect in female mice (P < 0.05). Similarly, intracerebroventricular FGF21 reduced TA muscle fiber cross sectional area (P < 0.01); this was more apparent among female mice compared to male littermates (P < 0.05). In agreement with the reduced muscle mass, the topmost enriched meta-bolic pathways in FGF21-treated females were related to amino acid metabolism, and the relative abundance of plasma proteinogenic amino acids were increased up to three-fold (P < 0.05). FGF21 treatment increased hypothalamic Crh mRNA (P < 0.01), plasma corticosterone (P < 0.01), and adrenal weight (P < 0.05), and increased expression of glucocorticoid receptor target genes known to reduce muscle protein synthesis and/or promote degradation including Foxo1, Redd1, and Klf15 (P < 0.05). Again, these changes were driven primarily by effects of FGF21 in females (P < 0.05). ConclusionsFGF21 increased plasma amino acids and decreased skeletal muscle mass, together with activation of the HPA axis and glucocorticoid receptor target genes in skeletal muscle--and female mice were more sensitive to all these outcomes. Given the proposed use of FGF21 analogues for the treatment of metabolic disease, the study is both physiologically relevant and may have important clinical implications.

physiology↗