Promotion of obesity by fibroblast growth factor 21-oxytocin system dysfunction due to sugar-specific hyperphagia.

Fibroblast growth factor (FGF) 21 activates oxytocin (OXT) neurons in the hypothalamus and suppresses simple sugar preference; however, alterations in the FGF21-OXT system in obesity remain unclear. In this study, we examined alterations in FGF21 secretion to systemic circulation and FGF21 sensitivity of OXT neurons in obesity, and the effects of FGF21-OXT dysfunction on feeding and body weight regulation. High-fat high-sucrose diet (HFHSD) feeding promoted hypersecretion of FGF21. The administration of recombinant FGF21 to normal diet-fed mice significantly activated OXT neurons in the paraventricular nucleus of the hypothalamus; this response was attenuated in HFHSD-fed mice. OXT neuron-specific FGF21 receptor-deficient (OXT cKO) mice were used as a model of FGF21-OXT dysfunction. The preference and appetite for sugar and fat were assessed using two-food choice test, two-bottle choice test, and lick microstructure analyses. The cKO mice showed an increased preference and appetite for FGF21-inducing simple sugars but not fat. These mice gained more weight when fed an HFHSD, which caused hyperphagia, but not when fed a high-fat diet. Therefore, obesity causes FGF21-OXT dysfunction, which promotes diet-induced obesity by increasing sugar appetite, suggesting that the dysfunction of the FGF21-OXT system plays a role in the vicious cycle of sugar-based diet-induced obesity in mice. FGF21 activates OXT neurons and suppresses simple sugar preference, but the relationship between FGF21-OXT system and obesity is unknown. Here, we showed that obesity causes FGF21-OXT dysfunction and promotes sugar appetite and diet-induced obesity, suggesting that there is a vicious cycle of FGF21-OXT dysfunction and obesity in mice.