Muscle very long-chain ceramides associate with insulin resistance independently of obesity
Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance (IR), however their precise roles remain unclear. Here, we leverage natural genetic variation to examine muscle lipids and systemic IR in 399 Diversity Outbred Australia mice fed either chow or a high-fa...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-09-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782500119X |
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| author | Søren Madsen Harry B. Cutler Kristen C. Cooke Meg Potter Jasmine Khor Christoph D. Rau Stewart WC. Masson Anna Howell Zora Modrusan Anthony S. Don Jacqueline Stöckli Alexis Diaz Vegas David E. James |
| author_facet | Søren Madsen Harry B. Cutler Kristen C. Cooke Meg Potter Jasmine Khor Christoph D. Rau Stewart WC. Masson Anna Howell Zora Modrusan Anthony S. Don Jacqueline Stöckli Alexis Diaz Vegas David E. James |
| author_sort | Søren Madsen |
| collection | DOAJ |
| description | Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance (IR), however their precise roles remain unclear. Here, we leverage natural genetic variation to examine muscle lipids and systemic IR in 399 Diversity Outbred Australia mice fed either chow or a high-fat diet. Adipose tissue mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs as the only lipid class enriched in this association. To disentangle the contribution of adiposity and muscle lipids to whole-body insulin sensitivity, we employed two independent approaches: (1) a linear model correcting muscle lipid features for adipose tissue mass to assess their relationship with insulin sensitivity, and (2) stratifying mice into insulin sensitivity quartiles within adiposity bins. Both revealed that very long-chain ceramides, but not DAGs, were linked to IR. RNA sequencing and proteomics from the same muscles further associated these very long-chain ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis. Meanwhile, DAGs correlated with leptin gene expression in skeletal muscle, suggesting they originate from contaminating adipocytes rather than myocytes per se. We propose that many muscle lipids, including DAGs, associate with muscle and systemic IR due to accumulation of adipose tissue rather than directly influencing muscle insulin sensitivity. By addressing the relationship between adiposity and metabolic state, we identified very long-chain muscle ceramides as being highly associated with IR independently of adiposity. |
| format | Article |
| id | doaj-art-7b1df5acd64a4042b1b923bef00cc8df |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-7b1df5acd64a4042b1b923bef00cc8df2025-08-20T03:38:58ZengElsevierMolecular Metabolism2212-87782025-09-019910221210.1016/j.molmet.2025.102212Muscle very long-chain ceramides associate with insulin resistance independently of obesitySøren Madsen0Harry B. Cutler1Kristen C. Cooke2Meg Potter3Jasmine Khor4Christoph D. Rau5Stewart WC. Masson6Anna Howell7Zora Modrusan8Anthony S. Don9Jacqueline Stöckli10Alexis Diaz Vegas11David E. James12School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia; Corresponding authors.School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaCharles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaComputational Medicine Program and Department of Human Genetics, University of North Carolina at Chapel Hill, United StatesSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaDepartment of Microchemistry, Proteomics, and Lipidomics, Genentech, South San Francisco, United StatesCharles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, AustraliaSchool of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia; Corresponding authors.School of Life and Environmental Sciences, University of Sydney, Camperdown, New South Wales, Australia; Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia; School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia; Corresponding authors.Lipids, in particular ceramides and diacylglycerols (DAGs), are implicated in insulin resistance (IR), however their precise roles remain unclear. Here, we leverage natural genetic variation to examine muscle lipids and systemic IR in 399 Diversity Outbred Australia mice fed either chow or a high-fat diet. Adipose tissue mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs as the only lipid class enriched in this association. To disentangle the contribution of adiposity and muscle lipids to whole-body insulin sensitivity, we employed two independent approaches: (1) a linear model correcting muscle lipid features for adipose tissue mass to assess their relationship with insulin sensitivity, and (2) stratifying mice into insulin sensitivity quartiles within adiposity bins. Both revealed that very long-chain ceramides, but not DAGs, were linked to IR. RNA sequencing and proteomics from the same muscles further associated these very long-chain ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis. Meanwhile, DAGs correlated with leptin gene expression in skeletal muscle, suggesting they originate from contaminating adipocytes rather than myocytes per se. We propose that many muscle lipids, including DAGs, associate with muscle and systemic IR due to accumulation of adipose tissue rather than directly influencing muscle insulin sensitivity. By addressing the relationship between adiposity and metabolic state, we identified very long-chain muscle ceramides as being highly associated with IR independently of adiposity.http://www.sciencedirect.com/science/article/pii/S221287782500119XInsulin resistanceSkeletal muscleLipidsCeramides |
| spellingShingle | Søren Madsen Harry B. Cutler Kristen C. Cooke Meg Potter Jasmine Khor Christoph D. Rau Stewart WC. Masson Anna Howell Zora Modrusan Anthony S. Don Jacqueline Stöckli Alexis Diaz Vegas David E. James Muscle very long-chain ceramides associate with insulin resistance independently of obesity Molecular Metabolism Insulin resistance Skeletal muscle Lipids Ceramides |
| title | Muscle very long-chain ceramides associate with insulin resistance independently of obesity |
| title_full | Muscle very long-chain ceramides associate with insulin resistance independently of obesity |
| title_fullStr | Muscle very long-chain ceramides associate with insulin resistance independently of obesity |
| title_full_unstemmed | Muscle very long-chain ceramides associate with insulin resistance independently of obesity |
| title_short | Muscle very long-chain ceramides associate with insulin resistance independently of obesity |
| title_sort | muscle very long chain ceramides associate with insulin resistance independently of obesity |
| topic | Insulin resistance Skeletal muscle Lipids Ceramides |
| url | http://www.sciencedirect.com/science/article/pii/S221287782500119X |
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