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Inhibition of Hypothalamic FTO Activates STAT3 Signal through ERK1/2 Associated with Reductions in Food Intake and

Fei Hu1, Hua-Juan Yan1, Cun-Xiu Gao1

  • 1Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Neuroendocrinology
|August 28, 2022
PubMed
Abstract

Insights

Inhibiting the FTO gene in the hypothalamus activates STAT3 via ERK1/2 signaling, reducing food intake and body weight. This discovery offers new insights into obesity control mechanisms.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • The Fat mass and obesity-associated (FTO) gene is strongly linked to obesity, a significant health concern.
  • Altered FTO protein expression in the hypothalamus affects appetite and body weight regulation, but its precise molecular mechanisms are unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which FTO influences appetite and body weight.
  • To explore the role of the ERK1/2 signaling pathway in FTO-mediated regulation of STAT3 phosphorylation.

Main Methods:

  • Utilized a mouse hypothalamic POMC cell line (N43/5) and in vivo mouse models.
  • Inhibited FTO using rhein or shRNA, and ERK1/2 using U0126.
  • Employed Western blotting, immunofluorescent assays, and intracerebroventricular cannulation.

Main Results:

  • FTO inhibition in N43/5 cells increased STAT3 phosphorylation at S727 and its nuclear translocation.
  • FTO inhibition enhanced ERK1/2 phosphorylation; blocking ERK1/2 abolished FTO inhibition's effects on STAT3.
  • Hypothalamic FTO inhibition in mice increased STAT3-S727 phosphorylation, reduced food intake, and decreased body weight. ERK1/2 inhibition counteracted these effects.

Conclusions:

  • Hypothalamic FTO inhibition activates STAT3 signaling through the ERK1/2 pathway.
  • This pathway is implicated in the reduction of food intake and body weight, suggesting a novel therapeutic target for obesity.
Keywords:
Body weightERK1/2FTOFood intakeHypothalamusSTAT3

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