Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand K. Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balážová, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S. Hamilton, Juan M. A. Alcántara, Jonatan R. Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Baláž, Atan Gross, Heike Neubauer, Christian Wolfrum
Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.