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<p>The metabolic effects of leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) remain largely unknown. Here, we showed that knockdown of <i>Lgr4</i> 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 <i>Lgr4</i> 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 <i>Lgr4</i> 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>

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Deficiency of neuronal LGR4 increases energy expenditure and inhibits food intake via hypothalamic leptin signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月11日

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  • Liping Zhang,
  • Yuan Li,
  • Wenbin Gao,
  • Ziru Li,
  • Tong Wu,
  • Chunhui Lang,
  • Liangyou Rui,
  • Weizhen Zhang

摘要

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.