A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat
Open accessAbstract
Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis. PAPERCLIP.
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Adipose tissue depots possess alternative futile cycles for increasing energy expenditure independent of UCP1.
“Studies within the past few years have demonstrated that adipose tissue depots possess alternative futile cycles for increasing energy expenditure independent of UCP1 (10, 58).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [58]
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- Authors
- Kazak, L., Chouchani, E. T., Jedrychowski, M. P., Erickson, B. K., Shinoda, K., Cohen, P., Vetrivelan, R., Lu, G. Z., Laznik-Bogoslavski, D., Hasenfuss, S. C., Kajimura, S., Gygi, S. P., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- University of California, San Francisco (US)
- Beth Israel Deaconess Medical Center (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 163
- Issue
- 3
- Pages
- 643-655
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4656041
- OpenAlex
- W2153276315
- Cited by
- 787
- References
- 36
- Citations by year
- 2026: 50 · 2025: 81 · 2024: 72 · 2023: 81 · 2022: 78 · 2021: 91 · 2020: 78 · 2019: 79 · 2018: 81 · 2017: 43 · 2016: 48 · 2015: 3 · 2012: 1
- FWCI
- 42.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- Canadian Institutes of Health Research
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK031405, P30DK098722, P30DK063720, R01DK108822, R37DK031405, R01DK097441, DK031405)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- creatine metabolism, beige adipose tissue, thermogenesis, energy expenditure, mitochondrial creatine kinase, cold exposure, UCP1, brown adipose tissue, mitochondrial respiration, beta3-adrenergic agonists, thermoregulation, mitochondrial proteomics
- MeSH terms
- Uncoupling Protein 1, Adenosine Diphosphate, Adipose Tissue, Animals, Adipose Tissue, Brown, Creatine, Energy Metabolism, Homeostasis, Humans, Ion Channels, Mitochondria, Obesity, Thermogenesis, Mitochondrial Proteins, Mice
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