Fibroblast growth factor 21 (FGF21) has a well-established role in modulating macronutrient uptake; it is produced by the liver in response to high-carbohydrate ingestion to signal to the brain to reduce carbohydrate intake and also has a role in modulating the preference for sweet-tasting foods and drinks. However, the neural pathways underlying these effects have been unclear. New work published in Cell Metabolism offers a potential mechanism for the effects of FGF21.
“In this work, we generated novel reporter mice, which allows us to identify all cells that FGF21 is capable of signalling to (β-Klotho (KLB)-Cre mice),” explains author Matthew Potthoff. “Using these mice, we performed single-cell RNA sequencing to identify these cells specifically in the brain, and then made a series of mutant mice in which we deleted the required FGF21 co-receptor (KLB) from specific types of neurons.” The researchers were able to demonstrate that FGF21 signalling to glutamatergic neurons in the hypothalamus is required to elicit a reduction in sugar intake in mice, and to alter their sweet taste preferences.
“Interestingly, we found that FGF21 signals to specific neurons in the hypothalamus to lower sugar intake by enhancing their sensitivity to glucose,” says Potthoff. Here, the researchers demonstrated that FGF21 has a direct effect on the ventromedial hypothalamus, which alters sugar intake but not sweet preference or energy expenditure. Wild-type mice were administered with either FGF21 or vehicle directly to the ventromedial hypothalamus. Only the mice that received FGF21 exhibited a significant reduction in sugar intake. The researchers also investigated whether FGF21 signalling in the ventromedial hypothalamus was important for energy homeostasis and weight loss by administering FGF21 to diet-induced obese wild-type mice and diet-induced obese KLB SF1-knockout mice (which have an impaired response to FGF21 in the hypothalamus). Similar effects were seen in both groups of mice, including reduced circulating levels of triglycerides, weight loss and improved insulin sensitivity. This finding indicates that FGF21 signalling in the ventromedial hypothalamus is not required to improve metabolic parameters or to induce weight loss.
“Going forward, we are particularly interested in identifying other brain regions that FGF21 acts on to regulate body weight (through increases in energy expenditure) and how FGF21 alters membrane excitability to achieve such potent and sustained effects on body weight regulation,” concludes Potthoff.
Jensen-Cody, S. O. et al. FGF21 signals to glutamatergic neurons in the ventromedial hypothalamus to suppress carbohydrate intake. Cell Metab. https://doi.org/10.1016/j.cmet.2020.06.008 (2020)
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Greenhill, C. Mechanism for the effects of FGF21. Nat Rev Endocrinol 16, 472 (2020). https://doi.org/10.1038/s41574-020-0396-y