A significant reduction in circulating leptin levels is well corelated with substantial weight loss. However, it is still not clear whether the observed leptin reduction is a cause or consequence of weight reduction. Here, we showed that FGF21 and liraglutide could rapidly induce leptin reduction, and this reduction contributes to the beneficial effects of FGF21 and liraglutide, as blocking the leptin reduction by a transgenic approach curtails the beneficial effects. Moreover, a higher degree of leptin reduction, induced by combination of leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, after removing liraglutide and FGF21, a significant weight gain is associated with rapid increase in circulating leptin levels and prevention of leptin surge by leptin neutralizing antibody slows down weight gain and preserves a better glucose tolerance. Mechanically, a significant reduction in leptin reduction induces a higher degree of leptin sensitivity in neurons, located in hypothalamic region, other than AP. In conclusion, this study supports a model that leptin reduction is required for substantial weight loss and partial leptin reduction may be a novel strategy to treat obesity and its associated metabolic syndromes.


S.Zhao: None. P.E.Scherer: None.

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