Identification of a molecular resistor that controls UCP1-independent Ca2+ cycling thermogenesis in adipose tissue
Adipose tissue thermogenesis contributes to energy balance via mitochondrial uncoupling protein 1 (UCP1) and UCP1-independent pathways. Among UCP1-independent thermogenic mechanisms, one involves Ca<sup>2+</sup> cycling via SERCA2b in adipose tissue; however, the underlying molecular basis remains elusive. Here, we report that an endoplasmic reticulum (ER) membrane-anchored peptide, C4orf3 (also known as another regulin [ALN]), uncouples SERCA2b Ca<sup>2+</sup> transport from its ATP hydrolysis, rendering the SERCA2b-C4orf3 complex exothermic. Loss of C4orf3/ALN improved the energetic efficiency of SERCA2b-dependent Ca<sup>2+</sup> transport without affecting SERCA2 expression, thereby reducing adipose tissue thermogenesis and increasing the adiposity of mice. Notably, genetic depletion of C4orf3 resulted in compensatory activation of UCP1-dependent thermogenesis following cold challenge. We demonstrated that genetic loss of both C4orf3 and Ucp1 additively impaired cold tolerance in vivo. Together, this study identifies C4orf3 as the molecular resistor to SERCA2b-mediated Ca<sup>2+</sup> import that plays a key role in UCP1-independent thermogenesis and energy balance.
Authors
- Patrick R. Griffin (ORCID: https://orcid.org/0000-0002-3404-690X)
- Satoshi Oikawa (ORCID: https://orcid.org/0000-0002-7696-8128)
- Kenji Inaba (ORCID: https://orcid.org/0000-0001-8229-0467)
- Roland H. Stimson (ORCID: https://orcid.org/0000-0002-9002-6188)
- Kosaku Shinoda (ORCID: https://orcid.org/0000-0002-1928-0749)
- Christopher Auger (ORCID: https://orcid.org/0000-0003-4207-9354)
- Anthony R.P. Verkerke (ORCID: https://orcid.org/0000-0002-6198-4723)
- Jin-Seon Yook (ORCID: https://orcid.org/0000-0002-9294-6770)
- Kenji Ikeda (ORCID: https://orcid.org/0000-0001-7877-9016)
- Timothy R. O’Leary (ORCID: https://orcid.org/0000-0001-7865-7705)
- Shingo Kajimura (ORCID: https://orcid.org/0000-0003-0672-5910)
- Mark Li (ORCID: https://orcid.org/0000-0002-7862-5460)
- Masanori Fujimoto (ORCID: https://orcid.org/0000-0003-1458-8207)
- María Paula Huertas Caycedo
- Cai Xiaohan
Institutions
- Scripps Research Institute (US)
- Tokyo Medical and Dental University (JP)
- Albert Einstein College of Medicine (US)
- Beth Israel Deaconess Medical Center (US)
- Howard Hughes Medical Institute (US)
- Japan Agency for Medical Research and Development (JP)
- The Queen's Medical Research Institute (GB)
- The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
- University of Edinburgh (GB)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1016/j.cmet.2025.03.009
- Citations
- 14
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 16.30