Glycogen metabolism links glucose homeostasis to thermogenesis in adipocytes

• Published in: Nature (London) 2021-11, Vol.599 (7884), p.296-301
• Main Authors: Keinan, Omer, Valentine, Joseph M., Xiao, Haopeng, Mahata, Sushil K., Reilly, Shannon M., Abu-Odeh, Mohammad, Deluca, Julia H., Dadpey, Benyamin, Cho, Leslie, Pan, Austin, Yu, Ruth T., Dai, Yang, Liddle, Christopher, Downes, Michael, Evans, Ronald M., Lusis, Aldons J., Laakso, Markku, Chouchani, Edward T., Rydén, Mikael, Saltiel, Alan R.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 38/77; 38/91; 631/443/319/1642/393; 631/443/319/2723; 64; 64/60; 96; 96/1; 96/106; 96/95; Adaptation, Physiological; Adipocytes; Adipocytes - metabolism; Adipocytes, Beige - metabolism; Adrenergic receptors; Animals; Body fat; Body mass index; Body weight loss; Catecholamines; Cold; Cold Temperature; Dextrose; Energy expenditure; Energy Metabolism; Enzymes; Fat cells; Female; Gene expression; Glucose; Glucose - metabolism; Glycogen; Glycogen - metabolism; Glycogens; Homeostasis; Humanities and Social Sciences; Humans; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Male; MAP kinase; Metabolism; Mice; Mice, Knockout; Mitochondria; multidisciplinary; Obesity; Oxygen; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Physiological research; Protein expression; Proteins; Reactive oxygen species; Receptors (physiology); Rodents; Scaffolding; Science; Science (multidisciplinary); Thermogenesis; Uncoupling protein 1; Uncoupling Protein 1 - metabolism; Weight control; Weight loss
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-04019-8

Adipocytes increase energy expenditure in response to prolonged sympathetic activation via persistent expression of uncoupling protein 1 (UCP1) 1 , 2 . Here we report that the regulation of glycogen metabolism by catecholamines is critical for UCP1 expression. Chronic β-adrenergic activation leads to increased glycogen accumulation in adipocytes expressing UCP1. Adipocyte-specific deletion of a scaffolding protein, protein targeting to glycogen (PTG), reduces glycogen levels in beige adipocytes, attenuating UCP1 expression and responsiveness to cold or β-adrenergic receptor-stimulated weight loss in obese mice. Unexpectedly, we observed that glycogen synthesis and degradation are increased in response to catecholamines, and that glycogen turnover is required to produce reactive oxygen species leading to the activation of p38 MAPK, which drives UCP1 expression. Thus, glycogen has a key regulatory role in adipocytes, linking glucose metabolism to thermogenesis. Increased glycogen metabolism in adipocytes leads to expression of uncoupling protein 1, thereby linking glucose metabolism to thermogenesis.