Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Biyi Chen
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Jinxi Wang
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Qingwen Qian
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa
Guangqin Zhang
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Yihui Wang
School of Life Sciences
Mark Li
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa
Rubin Tan
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Zhuoying Yang
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Weiyang Zhao
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Grace Ciampa
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Daniela Sarahi Yang Bennett
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Yixi Liu
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Qi Zhu
Zhiyong Zhu
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Sepiso K. Masenga
Department of Molecular Physiology and Biophysics, Vanderbilt University
Zer Vue
Department of Molecular Physiology and Biophysics, Vanderbilt University
Han Le
Department of Molecular Physiology and Biophysics, Vanderbilt University
Qian Shi
Leonid V. Zingman
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
Antentor O. Hinton
Department of Molecular Physiology and Biophysics, Vanderbilt University
Duane D. Hall
Division of Cardiovascular Medicine, Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa
E. Dale Abel
Ling Yang
Long-Sheng Song