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Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons

Author

Listed:
  • Hancheng Mao

    (University of Michigan Medical School)

  • Geun Hyang Kim

    (University of Michigan Medical School
    Regeneron Pharmaceuticals Inc.)

  • Linxiu Pan

    (University of Virginia, School of Medicine)

  • Ling Qi

    (University of Michigan Medical School
    University of Virginia, School of Medicine)

Abstract

Endoplasmic reticulum (ER) homeostasis in the hypothalamus has been implicated in the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes; however, the underlying molecular mechanism remain vague and debatable. Here we report that SEL1L-HRD1 protein complex of the highly conserved ER-associated protein degradation (ERAD) machinery in POMC-expressing neurons ameliorates diet-induced obesity and its associated complications, partly by regulating the turnover of the long isoform of Leptin receptors (LepRb). Loss of SEL1L in POMC-expressing neurons attenuates leptin signaling and predisposes mice to HFD-associated pathologies including fatty liver, glucose intolerance, insulin and leptin resistance. Mechanistically, nascent LepRb, both wildtype and disease-associated Cys604Ser variant, are misfolding prone and bona fide substrates of SEL1L-HRD1 ERAD. In the absence of SEL1L-HRD1 ERAD, LepRb are largely retained in the ER, in an ER stress-independent manner. This study uncovers an important role of SEL1L-HRD1 ERAD in the pathogenesis of central leptin resistance and leptin signaling.

Suggested Citation

  • Hancheng Mao & Geun Hyang Kim & Linxiu Pan & Ling Qi, 2024. "Regulation of leptin signaling and diet-induced obesity by SEL1L-HRD1 ER-associated degradation in POMC expressing neurons," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52743-2
    DOI: 10.1038/s41467-024-52743-2
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    1. Shuangcheng Alivia Wu & Chenchen Shen & Xiaoqiong Wei & Xiawei Zhang & Siwen Wang & Xinxin Chen & Mauricio Torres & You Lu & Liangguang Leo Lin & Huilun Helen Wang & Allen H. Hunter & Deyu Fang & Shen, 2023. "The mechanisms to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Kezhong Zhang & Randal J. Kaufman, 2008. "From endoplasmic-reticulum stress to the inflammatory response," Nature, Nature, vol. 454(7203), pages 455-462, July.
    3. Michael A. Cowley & James L. Smart & Marcelo Rubinstein & Marcelo G. Cerdán & Sabrina Diano & Tamas L. Horvath & Roger D. Cone & Malcolm J. Low, 2001. "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus," Nature, Nature, vol. 411(6836), pages 480-484, May.
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