{"title":"Deficiency of neuronal LGR4 increases energy expenditure and inhibits food intake via hypothalamic leptin signaling.","authors":"Liping Zhang, Yuan Li, Wenbin Gao, Ziru Li, Tong Wu, Chunhui Lang, Liangyou Rui, Weizhen Zhang","doi":"10.1038/s44319-025-00398-5","DOIUrl":null,"url":null,"abstract":"<p><p>The metabolic effects of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) remain largely unknown. Here, we showed that knockdown of Lgr4 in nestin progenitor or Sp1 mature neurons reduced high fat diet (HFD)-induced obesity by increasing energy expenditure and inhibiting food intake. Deficiency of LGR4 in AgRP neurons increased energy expenditure, and inhibited food intake, leading to alterations in glucose and lipid metabolism. Knock-down of Lgr4 in Sf1 neurons enhanced energy expenditure, reduced adiposity, and improved glucose and lipid metabolism. The metabolic benefits of neuronal LGR4 occurred via improvement of leptin signaling in AgRP and Sf1 neurons. Knockdown of Lgr4 in nestin, Sp1, AgRP or Sf1 neurons decreased hypothalamic levels of SOCS-3, and increased phosphorylation of STAT3. These alterations were associated with a significant reduction in the hypothalamic levels of β-catenin. Inhibition of β-catenin signaling by Dkk1 significantly attenuated the decrement of phospho-STAT3 and concurrent increase of SOCS-3 induced by Rspondin 3, an endogenous ligand for LGR4. Our results thus demonstrate that hypothalamic LGR4 may promote energy conversation by increasing food intake and decreasing energy expenditure. Deficiency of neuronal LGR4 improves hypothalamic leptin sensitivity via suppression of β-catenin signaling.</p>","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5000,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44319-025-00398-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
The metabolic effects of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) remain largely unknown. Here, we showed that knockdown of Lgr4 in nestin progenitor or Sp1 mature neurons reduced high fat diet (HFD)-induced obesity by increasing energy expenditure and inhibiting food intake. Deficiency of LGR4 in AgRP neurons increased energy expenditure, and inhibited food intake, leading to alterations in glucose and lipid metabolism. Knock-down of Lgr4 in Sf1 neurons enhanced energy expenditure, reduced adiposity, and improved glucose and lipid metabolism. The metabolic benefits of neuronal LGR4 occurred via improvement of leptin signaling in AgRP and Sf1 neurons. Knockdown of Lgr4 in nestin, Sp1, AgRP or Sf1 neurons decreased hypothalamic levels of SOCS-3, and increased phosphorylation of STAT3. These alterations were associated with a significant reduction in the hypothalamic levels of β-catenin. Inhibition of β-catenin signaling by Dkk1 significantly attenuated the decrement of phospho-STAT3 and concurrent increase of SOCS-3 induced by Rspondin 3, an endogenous ligand for LGR4. Our results thus demonstrate that hypothalamic LGR4 may promote energy conversation by increasing food intake and decreasing energy expenditure. Deficiency of neuronal LGR4 improves hypothalamic leptin sensitivity via suppression of β-catenin signaling.
期刊介绍:
EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings.
The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that:
Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels.
Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies.
Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding.
Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts.
EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.