Journal article
Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism
Proceedings of the National Academy of Sciences - PNAS, Vol.123(27), e2524943123
07/07/2026
DOI: 10.1073/pnas.2524943123
PMID: 42372139
Abstract
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.
Details
- Title: Subtitle
- Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism
- Creators
- Biyi Chen - University of IowaJinxi Wang - University of IowaQingwen Qian - University of IowaGuangqin Zhang - University of IowaYihui Wang - University of IowaMark Li - University of IowaRubin Tan - University of IowaZhuoying Yang - University of IowaWeiyang Zhao - University of IowaGrace Ciampa - University of IowaDaniela Sarahi Yang Bennett - University of IowaYixi Liu - University of IowaQi Zhu - University of IowaZhiyong Zhu - University of IowaSepiso K Masenga - University of IowaZer Vue - Vanderbilt UniversityHan Le - Vanderbilt UniversityQian Shi - University of IowaLeonid V Zingman - University of IowaAntentor O Hinton Jr - Vanderbilt UniversityDuane D Hall - University of IowaE Dale Abel - University of IowaLing Yang - University of IowaLong-Sheng Song - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.123(27), e2524943123
- DOI
- 10.1073/pnas.2524943123
- PMID
- 42372139
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences; WASHINGTON
- Grant note
- I01 BX006139 / BLRD VA R01 HL 168752 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) R01 HL181428 / NHLBI NIH HHS R01 HL157781 / NHLBI NIH HHS R01 HL130346 / NHLBI NIH HHS R01 HL180725 / NHLBI NIH HHS R01 HL157741 / NHLBI NIH HHS R01 DK126817-01A1 / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 07/07/2026
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9985177710802771
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