Single-nucleus transcriptomics identifies separate classes of UCP1 and futile cycle adipocytes

  • Cell Metab. 2024 Jul 26:S1550-4131(24)00276-6. doi: 10.1016/j.cmet.2024.07.005.
Tongtong Wang  1 ,  Anand Kumar Sharma  1 ,  Chunyan Wu  1 ,  Claudia Irene Maushart  2 ,  Adhideb Ghosh  1 ,  Wu Yang  3 ,  Patrik Stefanicka  4 ,  Zuzana Kovanicova  5 ,  Jozef Ukropec  5 ,  Jing Zhang  6 ,  Myrtha Arnold  1 ,  Manuel Klug  1 ,  Katrien De Bock  6 ,  Ulrich Schneider  7 ,  Cristina Popescu  8 ,  Bo Zheng  9 ,  Lianggong Ding  1 ,  Fen Long  1 ,  Revati Sumukh Dewal  1 ,  Caroline Moser  1 ,  Wenfei Sun  1 ,  Hua Dong  1 ,  Martin Takes  10 ,  Dominique Suelberg  7 ,  Alexander Mameghani  7 ,  Antonio Nocito  7 ,  Christoph Johannes Zech  10 ,  Alin Chirindel  10 ,  Damian Wild  10 ,  Irene A Burger  11 ,  Michael R Schön  12 ,  Arne Dietrich  13 ,  Min Gao  14 ,  Markus Heine  15 ,  Yizhi Sun  16 ,  Ariana Vargas-Castillo  16 ,  Susanna Søberg  17 ,  Camilla Scheele  17 ,  Miroslav Balaz  18 ,  Matthias Blüher  19 ,  Matthias Johannes Betz  20 ,  Bruce M Spiegelman  16 ,  Christian Wolfrum  21
Affiliations
  • 1. Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland.
  • 2. Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Basel and University of Basel, Basel, Switzerland.
  • 3. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 4. Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University in Bratislava, Bratislava, Slovakia.
  • 5. Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia.
  • 6. Laboratory of Exercise and Health, Health Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland.
  • 7. Department of Surgery, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland.
  • 8. Department of Nuclear Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland.
  • 9. School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China.
  • 10. Department of Radiology and Nuclear Medicine, University Hospital of Basel, Basel, Switzerland.
  • 11. Department of Nuclear Medicine, Cantonal Hospital of Baden, Im Ergel 1, 5404 Baden, Switzerland; Department of Nuclear Medicine, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
  • 12. Städtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, Karlsruhe, Germany.
  • 13. Clinic for Visceral, Transplant and Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstrasse 20, 04103 Leipzig, Germany.
  • 14. Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 15. Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
  • 16. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • 17. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark; The Center of Inflammation and Metabolism and the Center for Physical Activity Research, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.
  • 18. Institute of Experimental Endocrinology, Biomedical Research Center at the Slovak Academy of Sciences, Bratislava, Slovakia; Department of Animal Physiology and Ethology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
  • 19. Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Germany & Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital, Leipzig, Germany. Electronic address: [email protected].
  • 20. Department of Endocrinology, Diabetes, and Metabolism, University Hospital of Basel and University of Basel, Basel, Switzerland. Electronic address: [email protected].
  • 21. Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Department of Health Sciences and Technology ETH Zurich, Schwerzenbach, Switzerland. Electronic address: [email protected].
PMID: 39084216 DOI: 10.1016/j.cmet.2024.07.005
Abstract

Adipose tissue can recruit catabolic adipocytes that utilize chemical energy to dissipate heat. This process occurs either by uncoupled respiration through uncoupling protein 1 (UCP1) or by utilizing ATP-dependent futile cycles (FCs). However, it remains unclear how these pathways coexist since both processes rely on the mitochondrial membrane potential. Utilizing single-nucleus RNA Sequencing to deconvolute the heterogeneity of subcutaneous adipose tissue in mice and humans, we identify at least 2 distinct subpopulations of beige adipocytes: FC-adipocytes and UCP1-beige adipocytes. Importantly, we demonstrate that the FC-adipocyte subpopulation is highly metabolically active and utilizes FCs to dissipate energy, thus contributing to thermogenesis independent of Ucp1. Furthermore, FC-adipocytes are important drivers of systemic energy homeostasis and linked to glucose metabolism and obesity resistance in humans. Taken together, our findings identify a noncanonical thermogenic adipocyte subpopulation, which could be an important regulator of energy homeostasis in mammals.

Keywords
energy homeostasis; futile cycling; human metabolism; single-nucleus RNA sequencing; thermogenesis.
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