Fibroblast Growth Factor 21: Possible Role in Growth and Metabolic Development during Early Life, Nutritional Interactions and Biological Actions

Fibroblast growth factor 21 (FGF21) is a hormone produced mainly in the liver that plays a crucial role in systemic metabolic regulation. Its diverse metabolic functions include promoting glucose uptake in adipocytes, enhancing fat oxidation, and inducing thermogenesis. Studies in rodents have shown that treatment with FGF21 protects against diet-induced obesity and when overexpressed, can even extend lifespan. The relationship between FGF21 and dietary macronutrients is complex and bidirectional. Diets low in protein and high in carbohydrates, particularly simple sugars, strongly stimulate the production of FGF21. Evidence from rodent experiments shows that once secreted, FGF21 acts on the brain, stimulating protein intake and suppressing the preference for sugars. Compared with adults, the role of FGF21 in metabolic physiology and programming during early life is, however, less well understood. In human infants, linear growth is negatively correlated with circulating FGF21 concentrations. In mice, lipids present in breast milk stimulate the production of FGF21 after birth, possibly activating thermogenesis. In this narrative review, we delve into the topic of FGF21 and its significance for metabolic development and growth during early life, the nutritional regulation of FGF21, and its impact on macronutrient preferences. Given the strong link between protein intake and FGF21 signaling, we hypothesize that FGF21-mediated metabolic regulation could provide a mechanistic basis for the early protein hypothesis. This hypothesis posits that higher protein intake in infancy exacerbates weight gain and increases risk of cardiometabolic disease in later life. Here, we aim to contribute to a deeper understanding of FGF21 biology, highlighting its potential to enhance healthspan and longevity through nutritional modulation during early life.