Leptin Reduction as a Required Component for Weight Loss

Authors

Shangang Zhao
Na Li
Wei Xiong
Guannan Li
Sijia He
Zhuzhen Zhang
Qingzhang Zhu
Nisi Jiang
Christian Ikejiofor
Yi Zhu
May-Yun Wang
Xianlin Han
Ningyang Zhang
Carolina Solis-Herrera
Christine Kusminski
Zhiqiang An
Joel K Elmquist
Philipp E Scherer

Publication Date

2-1-2024

Journal

Diabetes

DOI

10.2337/db23-0571

PMID

37935033

PMCID

PMC10796304

PubMedCentral® Posted Date

11-7-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Mice, Leptin, Liraglutide, Obesity, Weight Loss, Glucose, Glucagon-Like Peptide-1 Receptor

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 glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide rapidly induced a reduction in leptin. This leptin reduction contributed to the beneficial effects of GLP-1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtailed 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 induced 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 was observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slowed down weight gain and preserved better glucose tolerance. Mechanistically, a significant reduction in leptin induced 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.