LepRb+ cell–specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice
Min-Hyun Kim, … , Wen-Shu Wu, Liangyou Rui
Min-Hyun Kim, … , Wen-Shu Wu, Liangyou Rui
Published December 13, 2022
Citation Information: J Clin Invest. 2023;133(4):e156722. https://doi.org/10.1172/JCI156722.
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Research Article Cell biology Metabolism

LepRb+ cell–specific deletion of Slug mitigates obesity and nonalcoholic fatty liver disease in mice

Abstract

Leptin exerts its biological actions by activating the long-form leptin receptor (LepRb). LepRb signaling impairment and leptin resistance are believed to cause obesity. The transcription factor Slug — also known as Snai2 — recruits epigenetic modifiers and regulates gene expression by an epigenetic mechanism; however, its epigenetic action has not been explored in leptin resistance. Here, we uncover a proobesity function of neuronal Slug. Hypothalamic Slug was upregulated in obese mice. LepRb+ cell–specific Slug-knockout (SlugΔLepRb) mice were resistant to diet-induced obesity, type 2 diabetes, and liver steatosis and experienced decreased food intake and increased fat thermogenesis. Leptin stimulated hypothalamic Stat3 phosphorylation and weight loss to a markedly higher level in SlugΔLepRb than in Slugfl/fl mice, even before their body weight divergence. Conversely, hypothalamic LepRb+ neuron–specific overexpression of Slug, mediated by AAV-hSyn-DIO-Slug transduction, induced leptin resistance, obesity, and metabolic disorders in mice on a chow diet. At the genomic level, Slug bound to and repressed the LepRb promoter, thereby inhibiting LepRb transcription. Consistently, Slug deficiency decreased methylation of LepRb promoter H3K27, a repressive epigenetic mark, and increased LepRb mRNA levels in the hypothalamus. Collectively, these results unravel what we believe to be a previously unrecognized hypothalamic neuronal Slug/epigenetic reprogramming/leptin resistance axis that promotes energy imbalance, obesity, and metabolic disease.

Authors

Min-Hyun Kim, Yuan Li, Qiantao Zheng, Lin Jiang, Martin G. Myers Jr., Wen-Shu Wu, Liangyou Rui

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Figure 1

Hypothalamic Slug is upregulated in obesity.

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Hypothalamic Slug is upregulated in obesity. (A) Representative X-gal st...
(A) Representative X-gal staining of SlugLacZ/+ mouse hypothalamic sections (n = 7 mice). (B and C) Representative hypothalamic images (n = 3 mice per group). Hypothalamic sections were prepared from SlugLacZ/+ mice and coimmunostained with antibodies to β-gal, NeuN, and GFAP as indicated. (D) VMH cell subpopulations were counted (n = 3 mice). (E) Hypothalamic Slug mRNA levels (normalized to 36B4 expression) in C57BL/6J male mice on a HFD for 15 weeks (n = 8 mice per group). a.u., arbitrary units. (F) Hypothalamic Slug mRNA levels in WT and ob/ob male mice at 14 weeks of age (n = 8 mice per group). (G and H) Hypothalamic sections were prepared from SlugLacZ/+ male mice (HFD for 3 weeks) and stained with anti–β-gal antibody. β-gal neurons in the VMH, DMH, and ARC were counted (n = 3 mice per group). Data are presented as mean ± SEM. *P < 0.05, 2-tailed unpaired Student’s t test.