Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism
Dysfunctional adipocyte calcium handling is implicated in obesity and thermogenesis. Junctophilins (JPs) stabilize calcium microdomain junctions between the plasma membrane and endoplasmic reticulum, but whether JPs are required for adipocyte function is not known. We show that JP2 is enriched in thermogenic brown adipose tissue (BAT) relative to other fat depots and is downregulated under conditions of nutrient overload. Conditional knockdown of JP2 in adipocytes, and more selectively in BAT, exacerbates cold intolerance and susceptibility to diet induced obesity. Mechanistically, JP2-depleted brown adipocytes exhibit calcium handling dysfunction with elevated cytosolic calcium levels at baseline but diminished norepinephrine-induced calcium transients, reduced store-operated calcium entry. Basal cytosolic calcium overload accounts for an increase in calpain activation and ensuing downregulation of STIM1 and hormone-sensitive lipase in JP2-depleted cells. Furthermore, JP2 silencing in brown adipocytes reduced oxygen consumption rates and compromised mitochondrial structure and quality. Together, these findings demonstrate that JP2 is essential for normal calcium homeostasis in brown adipocytes and reveal a critical role for JP2 in thermogenesis and resistance to diet-induced metabolic dysregulation.
Authors
- Sepiso K. Masenga (ORCID: https://orcid.org/0000-0003-4376-5831)
- Antentor Hinton (ORCID: https://orcid.org/0000-0002-7730-952X)
- Rubin Tan
- Guangqin Zhang (ORCID: https://orcid.org/0000-0002-0282-3807)
- Ling Yang (ORCID: https://orcid.org/0000-0002-3105-3063)
- Qian Shi (ORCID: https://orcid.org/0000-0003-2634-9553)
- Weiyang Zhao (ORCID: https://orcid.org/0000-0001-5707-376X)
- E. Dale Abel (ORCID: https://orcid.org/0000-0001-5290-0738)
- M LI
- Long‐Sheng Song (ORCID: https://orcid.org/0000-0002-6035-8106)
- Grace Ciampa (ORCID: https://orcid.org/0000-0001-5418-996X)
- Biyi Chen (ORCID: https://orcid.org/0000-0003-0402-7537)
- Duane D. Hall (ORCID: https://orcid.org/0000-0003-2228-0966)
- Leonid V. Zingman (ORCID: https://orcid.org/0000-0002-7566-4616)
- Jinxi Wang (ORCID: https://orcid.org/0000-0002-7349-6153)
- Zer Vue (ORCID: https://orcid.org/0000-0002-3502-8906)
- Yihui Wang (ORCID: https://orcid.org/0000-0002-7718-3816)
- Qi Zhu (ORCID: https://orcid.org/0000-0003-3965-8419)
- Zhiyong Zhu (ORCID: https://orcid.org/0009-0009-7671-7490)
- Qingwen Qian
- D. Bennett
- Zhuoying Yang
- Yixi Liu
- Han Le
Institutions
- University of Iowa (US)
- University of California, Los Angeles (US)
- Vanderbilt University (US)
- Veterans Health Administration (US)
- Fraternal Order of Eagles (US)
- ABB (United States) (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-06-29
- DOI
- https://doi.org/10.1073/pnas.2524943123
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Veterans Affairs
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases