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An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity

Yuzhong Xiao1, Yalan Deng1, Feixiang Yuan1

  • 1a Key Laboratory of Nutrition and Metabolism , Institute for Nutritional Sciences, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences , Shanghai , China.

Autophagy
|March 29, 2017
PubMed

Insights

Activating transcription factor 4 (ATF4) deletion in hypothalamic POMC neurons promotes leanness and energy expenditure. This suggests ATF4 is a potential therapeutic target for obesity and metabolic disorders.

Area of Science:

  • Neuroscience
  • Metabolism
  • Molecular Biology

Background:

  • The role of activating transcription factor 4 (ATF4) in hypothalamic pro-opiomelanocortin (POMC) neurons regarding energy homeostasis remains unexplored.
  • POMC neurons in the hypothalamus are crucial for regulating energy balance and body weight.

Purpose of the Study:

  • To investigate the function of ATF4 in POMC neurons for energy homeostasis.
  • To explore ATF4's role in diet-induced obesity and related metabolic dysfunction.

Main Methods:

  • Generation of POMC-neuron-specific Atf4 knockout mice (PAKO mice).
  • Assessment of energy expenditure, body weight, and metabolic parameters under normal and high-fat diet (HFD) conditions.
  • Analysis of autophagy-related gene 5 (ATG5) expression and its regulation by ATF4 in POMC neurons.
  • Generation of POMC-neuron-specific Atf4 and Atg5 double knockout mice.

Main Results:

  • PAKO mice exhibited reduced body weight, increased energy expenditure, and resistance to HFD-induced obesity.
  • ATF4 directly binds to the promoter of ATG5, upregulating its expression in POMC neurons.
  • Mice lacking both Atf4 and Atg5 in POMC neurons showed reduced energy expenditure and increased fat mass under HFD compared to PAKO mice.
  • Atf4 knockout in POMC neurons enhanced ATG5-dependent autophagy and α-melanocyte-stimulating hormone (α-MSH) production.

Conclusions:

  • ATF4 plays a beneficial role in hypothalamic POMC neurons, regulating obesity and energy expenditure.
  • Enhanced ATG5-dependent autophagy and α-MSH production mediate the effects of Atf4 deletion in POMC neurons.
  • Targeting ATF4 in POMC neurons presents a potential therapeutic strategy for obesity and metabolic diseases.
Keywords:
ATF4ATG5POMC neuronsautophagyobesity

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