Fgf-21 mediates liver-hypothalamus communication and may determine the metabolic phenotype.

Early-life determinants are thought to be a major factor in the rapid increase of obesity. However, while maternal nutrition has been extensively studied, the effects of breastfeeding by the infant on the reprogramming of energy balance in childhood/adulthood remain largely unknown. The preclinical model of delayed weaning in pups protects individuals against obesity in adulthood by activating BAT thermogenesis and the browning of WAT, reducing body weight and fat mass, and improving glucose tolerance and leptin sensitivity, without altering food intake. These effects of prolonged suckling are mediated by increased hepatic FGF21 production and access to the hypothalamus in adulthood. It was shown that in the median eminence, extravasating FGF21 is taken up by tanycytes, specialized cells that connect the pituitary portal blood vessels to the third ventricle and are known to actively transport circulating peptide hormones into the CNS in a highly regulated manner. Once in the hypothalamus, FGF21 acts on GABAergic D2R-expressing neurons of the LHA/ZI, which also express the FGF21 receptor FGFR1, to exert its effects on body weight and thermogenesis. In addition to creating new avenues for intervention to improve the metabolic outcome of infants exposed to HFD, these findings lay the foundations of a better understanding of the mechanisms underlying long-term physiological remodeling by early-life events, with multiple potential health benefits. None