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

Autor: Mao H; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA., Kim GH; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA.; Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Road, Tarrytown, New York, NY, 10591, USA., Pan L; Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA, 22903, USA., Qi L; Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48105, USA. xvr2hm@virginia.edu.; Department of Molecular Physiology and Biological Physics, University of Virginia, School of Medicine, Charlottesville, VA, 22903, USA. xvr2hm@virginia.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 29; Vol. 15 (1), pp. 8435. Date of Electronic Publication: 2024 Sep 29.
DOI: 10.1038/s41467-024-52743-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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