Leptin Reduction as a Required Component for Weight Loss.

Abstract

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtails the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induces greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain is observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slows down weight gain and preserves a better glucose tolerance. Mechanistically, a significant reduction in leptin induces a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.