Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis
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Abstract
Cold-induced thermogenesis is an energy-demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted liquid chromatography-mass spectrometry-based lipidomics, we identified elevated levels of plasma acylcarnitines in response to the cold. We found that the liver undergoes a metabolic switch to provide fuel for brown fat thermogenesis by producing acylcarnitines. Cold stimulates white adipocytes to release free fatty acids that activate the nuclear receptor HNF4α, which is required for acylcarnitine production in the liver and adaptive thermogenesis. Once in circulation, acylcarnitines are transported to brown adipose tissue, while uptake into white adipose tissue and liver is blocked. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlight an elegant mechanism whereby white adipose tissue provides long-chain fatty acids for hepatic carnitilation to generate plasma acylcarnitines as a fuel source for peripheral tissues in mice.
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Upon cold exposure, WAT produces free fatty acids that promote hepatic acylcarnitine production; these acylcarnitines are used by BAT for adaptive thermogenesis.
“In one instance, Simcox and colleagues showed that upon cold exposure, WAT produces free fatty acids that, in turn, promote hepatic acylcarnitine production. These acylcarnitines are in fine used by BAT for adaptive thermogenesis 163.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [163]
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- Authors
- Simcox, J., Geoghegan, G., Maschek, J. A., Bensard, C. L., Pasquali, M., Miao, R., Lee, S., Jiang, L., Huck, I., Kershaw, E. E., Donato, A. J., Apte, U., Longo, N., Rutter, J., Schreiber, R., Zechner, R., Cox, J., & Villanueva, C. J.
- Affiliations
- University of Utah (US)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- University of Kansas Medical Center (US)
- University of Pittsburgh (US)
- VA Salt Lake City Healthcare System (US)
- University of Graz (AT)
- Corresponding author
- Villanueva, Claudio J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 26
- Issue
- 3
- Pages
- 509-522.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5658052
- OpenAlex
- W2611486163
- Cited by
- 277
- References
- 76
- Citations by year
- 2026: 23 · 2025: 34 · 2024: 33 · 2023: 43 · 2022: 32 · 2021: 35 · 2020: 34 · 2019: 21 · 2018: 19 · 2017: 3
- FWCI
- 15.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIDDK (KO1DK097285, RO3DK103089, RO1DK103930, T32DK091317, S10 OD016232-01)
- 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 › Peroxisome Proliferator-Activated Receptors
- Keywords
- acylcarnitines, brown adipose tissue thermogenesis, cold-induced thermogenesis, HNF4α, white adipose tissue, free fatty acid release, plasma lipidomics, L-carnitine, palmitoylcarnitine, aging, long-chain fatty acids
- MeSH terms
- Aging, Animals, Body Temperature, Adipose Tissue, Brown, Carnitine, Carnitine O-Palmitoyltransferase, Citric Acid Cycle, Cold Temperature, Fatty Acids, Gene Expression Regulation, Lipids, Lipolysis, Liver, Phenotype, Time Factors, Thermogenesis, Mice, Hepatocyte Nuclear Factor 4, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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