An Alternative Neural Basis Underlying Leptin Resistance

Authors

Hongli Li
Cunjin Su
Yuanzhong Xu
Mette Q Ludwig
Jon Davis
Qingchun Tong

Publication Date

7-22-2025

Journal

Cell Reports

DOI

10.1016/j.celrep.2025.115863

PMID

40540394

PMCID

PMC12337207

PubMedCentral® Posted Date

8-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (ArcGABA) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of ArcGABA neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of ArcGABA non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin levels failing to reduce obesity. In contrast, chronic inhibition of ArcGABA non-LepR neurons effectively prevented and reversed DIO, suggesting a potential anti-obesity treatment strategy. These results reveal that obesogenic stimulation of ArcGABA non-LepR neurons, even with intact leptin-pSTAT3 signaling, results in obesity, identifying a novel neural basis underlying leptin resistance.

Keywords

Leptin, Animals, Obesity, STAT3 Transcription Factor, Receptors, Leptin, Mice, GABAergic Neurons, Mice, Inbred C57BL, Male, Arcuate Nucleus of Hypothalamus, Signal Transduction

Published Open-Access

yes

Recommended Citation

Li, Hongli; Su, Cunjin; Xu, Yuanzhong; et al., "An Alternative Neural Basis Underlying Leptin Resistance" (2025). Faculty, Staff and Student Publications. 5058.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5058