Abstract
Adipose tissue plays an essential role in metabolic health. Ames dwarf mice are exceptionally long-lived and display metabolically beneficial phenotypes in their adipose tissue, providing an ideal model for studying the intersection between adipose tissue and longevity. To this end, we assessed the metabolome and lipidome of adipose tissue in Ames dwarf mice. We observed distinct lipid profiles in brown versus white adipose tissue of Ames dwarf mice that are consistent with increased thermogenesis and insulin sensitivity, such as increased cardiolipin and decreased ceramide concentrations. Moreover, we identified 5-hydroxyeicosapentaenoic acid (5-HEPE), an ω-3 fatty acid metabolite, to be increased in Ames dwarf brown adipose tissue (BAT), as well as in circulation. Importantly, 5-HEPE is increased in other models of BAT activation and is negatively correlated with body weight, insulin resistance, and circulating triglyceride concentrations in humans. Together, these data represent a novel lipid signature of adipose tissue in a mouse model of extreme longevity.
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Funding
This work was supported in part by U.S. NIH grants R01DK077097 and R01DK102898, and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.), and by grant P30DK036836 (to Joslin Diabetes Center’s Diabetes Research Center; DRC) from the National Institute of Diabetes and Digestive and Kidney Diseases. J.D. was supported by NIH grant T32DK007260 and American Heart Association grant 20POST35210497. M.D.L. was supported by NIH grant K01DK111714.
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J.D. designed and directed research, performed experiments, analyzed data, and wrote the paper. Y.F., S.M., and A.B. designed research and performed experiments with Ames dwarf mice. M.D.L. and L.O.L. performed experiments with the Myf5CreBMPr1afl/fl mice. J.M.D. aided in the creation of the online viewer. N.R.N. oversaw lipidomic and metabolomic experiments. V.B. and M.A.K. performed lipidomic analysis and experimentation. V.T. and B.G. performed metabolomic analysis and experimentation. Y.-H.T. directed the research and co-wrote the paper.
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All animal procedures were approved by the Institutional Animal Care and Use Committees at the Joslin Diabetes Center (JDC) and Southern Illinois University School of Medicine (SIUSOM). The collection of the human samples, phenotyping, and serum analyses were approved by the ethics committee of the University of Leipzig (approval numbers: 159-12-21052012 and 017-12-23012012). All individuals provided written informed consent prior to entering the study.
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The authors declare the following competing interests: M.A.K., N.R.N., V.T., B.G., and V.B. are employees of BERG.
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Supplemental Fig 1
Metabolite distribution in Ames dwarf adipose tissue A. Heatmap of the top 50 altered metabolites (by Student’s t test) in BAT between Ames dwarf mice and control littermates. Each column represents one animal, and each row represents one metabolite (n = 6 per group). B. Heatmap of the top 50 altered metabolites in iWAT between Ames dwarf mice and control littermates (n = 6 control and 9 dwarf). C. Volcano plot of metabolites from BAT in dwarfs vs controls displayed as the log base-2 ratio of dwarf to control versus the inverse log base-10 of the P value of this comparison (Student’s t test). A P value of 0.05 is indicated by a dotted line. (n = 6 per group). D. Volcano plot of metabolites from iWAT (n = 6 control and 9 dwarfs per group). (PNG 6168 kb)
Supplemental Fig 2
Lipid distribution in Ames dwarf adipose tissue A. The breakdown of each lipid class quantified in BAT of Ames dwarf mice. The lipid classes are acylcarnitine (AC), ceramide (Cer), cholesterol ester (CE), coenzyme Q (CoQ), monoacylglycerol (MAG), diacylglycerol (DAG), triacylglycerol (TAG), free fatty acid (FFA), glycolipid, phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), cardiolipin (CL), and branched fatty acid esters of hydroxy fatty acids (FAHFA). B. The breakdown of each lipid class quantified in iWAT of Ames dwarf mice. C. Volcano plot of structural lipids from BAT in dwarfs vs controls displayed as the log base-2 ratio of dwarf to control versus the inverse log base-10 of the P value of this comparison (Student’s t test). A P value of 0.05 is indicated by a dotted line. Cer, CL, FAHFA, and phospholipid family members are denoted (n = 5 controls and 6 dwarfs per group). D. Volcano plot of structural lipids from iWAT (n = 6 control and 9 dwarfs per group). (PNG 6168 kb)
Supplemental Fig 3
Ames dwarf mice have unaltered phospholipids in their BAT A. Concentrations of phospholipids in BAT of Ames dwarf mice. B. Concentrations of lyso-containing phospholipids in BAT of Ames dwarf mice. C. Concentrations of saturated phospholipids in BAT of Ames dwarf mice. D. Concentrations of monounsaturated phospholipids in BAT of Ames dwarf mice. E. Concentrations of polyunsaturated phospholipids in BAT of Ames dwarf mice. F. Concentrations of phospholipids containing 18:2 in BAT of Ames dwarf mice. G. Concentrations of phospholipids containing 20:4 in BAT of Ames dwarf mice. H. Concentrations of phospholipids containing 22:6 in BAT of Ames dwarf mice. Data throughout the figure are presented as mean ± SEM; n = 6 control and 5 dwarf. *P < 0.05, **P < 0.01, by Student’s t test. (PNG 6168 kb)
Supplemental Table 1
Metabolomic dataset of thermogenic adipose tissue in Ames dwarf mice A list of all quantified metabolites for BAT and iWAT of Ames dwarf mice. Values shown are normalized values. (XLSX 119 kb)
Supplemental Table 2
Structural lipids in BAT of Ames dwarf mice A list of structural lipids in BAT in Ames dwarf mice. (XLSX 260 kb)
Supplemental Table 3
Structural lipids in iWAT of Ames dwarf mice A list of structural lipids in BAT in Ames dwarf mice. (XLSX 294 kb)
Supplemental Table 4
Oxylipins in adipose tissue and serum of Ames dwarf mice A list of oxylipins in BAT, iWAT, and serum of Ames dwarf mice. (XLSX 81 kb)
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Darcy, J., Fang, Y., McFadden, S. et al. Integrated metabolomics reveals altered lipid metabolism in adipose tissue in a model of extreme longevity. GeroScience 42, 1527–1546 (2020). https://doi.org/10.1007/s11357-020-00221-0
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DOI: https://doi.org/10.1007/s11357-020-00221-0