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

TL;DR

Reducing LGR4 in neurons improves energy use and reduces obesity by boosting leptin signaling in the brain.

Contribution

This study reveals that neuronal LGR4 deficiency enhances leptin sensitivity via β-catenin suppression, combating obesity.

Findings

LGR4 deficiency in AgRP and Sf1 neurons increases energy expenditure and reduces food intake.

Neuronal LGR4 suppression improves glucose and lipid metabolism in high-fat diet models.

LGR4 inhibits leptin signaling through β-catenin in the hypothalamus.

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.

Neuronal deficiency of LGR4 improves hypothalamic leptin sensitivity via suppression of β- catenin signaling, which subsequently increases energy expenditure and decreases food intake, thus rendering mice resistant to high fat diet (HFD)-induced obesity.

Depletion of Lgr4 in nestin or Sp1 neurons renders mice resistant to HFD-induced obesity.Depletion of Lgr4 in AgRP neurons increases energy expenditure and inhibits food intake.Depletion of Lgr4 in Sf1 neurons increases energy expenditure.Intrascapular BAT bilateral sympathectomy attenuates metabolic benefits of LGR4 deficiency in AgRP or Sf1 neurons.Depletion of Lgr4 in nestin, Sp1, AgRP or Sf1 neurons reverses the downregulation of hypothalamic leptin signaling induced by HFD.LGR4 suppresses hypothalamic leptin signaling via β-catenin.

Depletion of Lgr4 in nestin or Sp1 neurons renders mice resistant to HFD-induced obesity.

Depletion of Lgr4 in AgRP neurons increases energy expenditure and inhibits food intake.

Depletion of Lgr4 in Sf1 neurons increases energy expenditure.

Intrascapular BAT bilateral sympathectomy attenuates metabolic benefits of LGR4 deficiency in AgRP or Sf1 neurons.

Depletion of Lgr4 in nestin, Sp1, AgRP or Sf1 neurons reverses the downregulation of hypothalamic leptin signaling induced by HFD.

LGR4 suppresses hypothalamic leptin signaling via β-catenin.

Neuronal deficiency of LGR4 improves hypothalamic leptin sensitivity via suppression of β- catenin signaling, which subsequently increases energy expenditure and decreases food intake, thus rendering mice resistant to high fat diet (HFD)-induced obesity.

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