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Sex- and strain-specific effects of mitochondrial uncoupling on age-related metabolic diseases in high-fat diet-fed mice

Goedeke, Leigh, Murt, Kelsey N., Di Francesco, Andrea, Camporez, João Paulo, Nasiri, Ali R., Wang, Yongliang, Zhang, Xian‐Man, Cline, Gary W., de Cabo, Rafael, Shulman, Gerald I.·2022·Aging Cell
DOI 10.1111/acel.13539PMC PMC8844126
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Abstract

Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria and may have evolved to protect cells against the production of damaging reactive oxygen species. Therefore, compounds that enhance mitochondrial uncoupling are potentially attractive anti‐aging therapies; however, chronic ingestion is associated with a number of unwanted side effects. We have previously developed a controlled‐release mitochondrial protonophore (CRMP) that is functionally liver‐directed and promotes oxidation of hepatic triglycerides by causing a subtle sustained increase in hepatic mitochondrial inefficiency. Here, we sought to leverage the higher therapeutic index of CRMP to test whether mild mitochondrial uncoupling in a liver‐directed fashion could reduce oxidative damage and improve age‐related metabolic disease and lifespan in diet‐induced obese mice. Oral administration of CRMP (20 mg/[kg‐day] × 4 weeks) reduced hepatic lipid content, protein kinase C epsilon activation, and hepatic insulin resistance in aged (74‐week‐old) high‐fat diet (HFD)‐fed C57BL/6J male mice, independently of changes in body weight, whole‐body energy expenditure, food intake, or markers of hepatic mitochondrial biogenesis. CRMP treatment was also associated with a significant reduction in hepatic lipid peroxidation, protein carbonylation, and inflammation. Importantly, long‐term (49 weeks) hepatic mitochondrial uncoupling initiated late in life (94–104 weeks), in conjugation with HFD feeding, protected mice against neoplastic disorders, including hepatocellular carcinoma (HCC), in a strain and sex‐specific manner. Taken together, these studies illustrate the complex variation of aging and provide important proof‐of‐concept data to support further studies investigating the use of liver‐directed mitochondrial uncouplers to promote healthy aging in humans.

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FIGURE 1 Effect of CRMP on metabolic syndrome in aged HFD‐fed male C57BL/6J mice. (a) C57BL/6J 74‐week‐old male mice were fed a high‐fat diet (HFD, 45% fat) for 8 weeks and then treated with CRMP (20 mg/[kg‐day]) or vehicle control for an additional 4 weeks. (b) Tissue concentrations of DNP in 6 h fasted CRMP‐treated mice. Body weight (c), % fat mass (d), % lean mass (e), plasma insulin (f), FPG (g), plasma triglycerides (h), plasma total cholesterol (i), plasma HDL‐C (j), β‐OHB (k), and BUN (l) in 6 h fasted aged male mice treated as in (a). In all panels, data are presented as mean ± SEM. n = 2 (b), 10–15 (c, h‐i), 10–13 per group (d‐e, k), 14–16 per group (f), 15–20 (g), 7–9 per treatment group (j), and 7–8 (l) per treatment group. β‐OHB, β‐hydroxybutyrate; CRMP, controlled‐release mitochondrial protonophore; DNP, 2, 4‐dinitrophenol; FPG, fasting plasma glucose; HFD, high‐fat diet
FIGURE 1 Effect of CRMP on metabolic syndrome in aged HFD‐fed male C57BL/6J mice. (a) C57BL/6J 74‐week‐old male mice were fed a high‐fat diet (HFD, 45% fat) for 8 weeks and then treated with CRMP (20 mg/[kg‐day]) or vehicle control for an additional 4 weeks. (b) Tissue concentrations of DNP in 6 h fasted CRMP‐treated mice. Body weight (c), % fat mass (d), % lean mass (e), plasma insulin (f), FPG (g), plasma triglycerides (h), plasma total cholesterol (i), plasma HDL‐C (j), β‐OHB (k), and BUN (l) in 6 h fasted aged male mice treated as in (a). In all panels, data are presented as mean ± SEM. n = 2 (b), 10–15 (c, h‐i), 10–13 per group (d‐e, k), 14–16 per group (f), 15–20 (g), 7–9 per treatment group (j), and 7–8 (l) per treatment group. β‐OHB, β‐hydroxybutyrate; CRMP, controlled‐release mitochondrial protonophore; DNP, 2, 4‐dinitrophenol; FPG, fasting plasma glucose; HFD, high‐fat dietCC BY · PubMed Central
FIGURE 2 CRMP improves hepatic insulin sensitivity in aged HFD‐fed male C57BL/6J mice. (a–b) Plasma glucose and glucose infusion rate (GIR) during a hyperinsulinemic‐euglycemic clamp (3 mU/[kg‐min]) in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. (c) Whole‐body glucose uptake in aged male mice treated as in (a). (d) EGP during the basal and steady‐state period of the clamp. (e) Insulin‐mediated suppression of EGP during the clamp. (f) Plasma NEFA levels during the basal and steady‐state period of the clamp. (g) Insulin‐mediated suppression of plasma NEFAs during the clamp. Whole‐body FFA (h) and glycerol (i) turnover during the basal and steady‐state period of the clamp. In all panels, data are presented as mean ± SEM. n = 14–20 (a–e), 8–9 (f–g), and 6–10 (h–i) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; EGP, endogenous glucose production; FFA, free fatty acids; GIR, glucose infusion rate; HFD, high‐fat diet; NEFA, non‐esterified fatty acids
FIGURE 2 CRMP improves hepatic insulin sensitivity in aged HFD‐fed male C57BL/6J mice. (a–b) Plasma glucose and glucose infusion rate (GIR) during a hyperinsulinemic‐euglycemic clamp (3 mU/[kg‐min]) in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. (c) Whole‐body glucose uptake in aged male mice treated as in (a). (d) EGP during the basal and steady‐state period of the clamp. (e) Insulin‐mediated suppression of EGP during the clamp. (f) Plasma NEFA levels during the basal and steady‐state period of the clamp. (g) Insulin‐mediated suppression of plasma NEFAs during the clamp. Whole‐body FFA (h) and glycerol (i) turnover during the basal and steady‐state period of the clamp. In all panels, data are presented as mean ± SEM. n = 14–20 (a–e), 8–9 (f–g), and 6–10 (h–i) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; EGP, endogenous glucose production; FFA, free fatty acids; GIR, glucose infusion rate; HFD, high‐fat diet; NEFA, non‐esterified fatty acidsCC BY · PubMed Central
FIGURE 3 Liver‐directed mitochondrial uncoupling reduces hepatic ectopic lipid content in aged HFD‐fed male C57BL/6J mice. Hepatic triglyceride (a), diacylglycerol (b), and ceramide (c) content in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. (d) Representative Western blot of PKCε membrane to cytosol translocation in livers of aged mice treated as in (a). GAPDH and ATPase were used as loading controls. Quantification shown in panel (e). (f) Representative Western blot of pAKTS473/AKT in the livers of clamped aged mice treated as in (a). Quantification shown in panel (g). In all panels, data are presented as mean ± SEM. n = 7–9 (a–c), 10–15 (d–e), 10–13 (d–e), and 8–9 (f–g) per treatment group. *p < .05 by two‐sided unpaired Student's t test (a, e, g) or Mann–Whitney test (b) compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; HFD, high‐fat diet
FIGURE 3 Liver‐directed mitochondrial uncoupling reduces hepatic ectopic lipid content in aged HFD‐fed male C57BL/6J mice. Hepatic triglyceride (a), diacylglycerol (b), and ceramide (c) content in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. (d) Representative Western blot of PKCε membrane to cytosol translocation in livers of aged mice treated as in (a). GAPDH and ATPase were used as loading controls. Quantification shown in panel (e). (f) Representative Western blot of pAKTS473/AKT in the livers of clamped aged mice treated as in (a). Quantification shown in panel (g). In all panels, data are presented as mean ± SEM. n = 7–9 (a–c), 10–15 (d–e), 10–13 (d–e), and 8–9 (f–g) per treatment group. *p < .05 by two‐sided unpaired Student's t test (a, e, g) or Mann–Whitney test (b) compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; HFD, high‐fat dietCC BY · PubMed Central
FIGURE 4 CRMP reduces hepatic inflammation and markers of oxidative stress in aged HFD‐fed male C57BL/6J mice. Plasma ALT (a), plasma AST (b), hepatic cytokine expression (c), hepatic protein carbonyl content (d), hepatic MDA (e), hepatic GSH/GSSG ratio (f), and hepatic oxo8dG/105dG (g) in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. In all panels, data are presented as mean ± SEM. n = 7–9 (a–b, d), 6 (c), 7–11 (e), 9–10 (f), and 10 (g) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; HFD, high‐fat diet; MDA, malondialdehyde; GSH, glutathione; GSSG, glutathione disulfide; 8oxo8dG, 8‐Oxo‐7,8‐dihydro‐2′‐deoxyguanosine
FIGURE 4 CRMP reduces hepatic inflammation and markers of oxidative stress in aged HFD‐fed male C57BL/6J mice. Plasma ALT (a), plasma AST (b), hepatic cytokine expression (c), hepatic protein carbonyl content (d), hepatic MDA (e), hepatic GSH/GSSG ratio (f), and hepatic oxo8dG/105dG (g) in aged HFD‐fed male C57BL/6J mice treated with CRMP (20 mg/[kg‐day]) for 4 weeks. In all panels, data are presented as mean ± SEM. n = 7–9 (a–b, d), 6 (c), 7–11 (e), 9–10 (f), and 10 (g) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control. CRMP, controlled‐release mitochondrial protonophore; HFD, high‐fat diet; MDA, malondialdehyde; GSH, glutathione; GSSG, glutathione disulfide; 8oxo8dG, 8‐Oxo‐7,8‐dihydro‐2′‐deoxyguanosineCC BY · PubMed Central
FIGURE 5 Sex‐ and strain‐specific effects of CRMP on age‐related metabolic disease in HFD‐fed mice. (a) Schematic diagram outlining long‐term aging study. 94–104 week‐old male and female F1 offspring of DBA/2J (D2) and C57BL/6J (B6) mice were fed a high‐fat diet (45% fat, HFD) or HFD containing CRMP (10 mg/[kg‐day]) for the remainder of their lives (~12 months). (b) Plasma DNP concentrations in 6 h fasted CRMP‐treated D2B6 and B6D2 mice. (c–j) Body weight (c–f) and body temperature (g–j) trajectories in D2B6 and B6D2 male and female mice. (K–L) 6 h FPG (K) and insulin (L) in D2B6 and B6D2 male and female mice treated for 3 months with CRMP (10 mg/[kg‐day]) or vehicle control. In all panels, data are presented as mean ± SEM. n = 4 (b), 11–29 (c‐j), 7–18 (k), and 7–11 (l) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control (d, g–j). Abbreviations: C57BL/6J (B6); CRMP, controlled‐release mitochondrial protonophore; DBA/2J (D2); DNP, 2, 4‐dinitrophenol; FPG, fasting plasma glucose; HFD, high‐fat diet
FIGURE 5 Sex‐ and strain‐specific effects of CRMP on age‐related metabolic disease in HFD‐fed mice. (a) Schematic diagram outlining long‐term aging study. 94–104 week‐old male and female F1 offspring of DBA/2J (D2) and C57BL/6J (B6) mice were fed a high‐fat diet (45% fat, HFD) or HFD containing CRMP (10 mg/[kg‐day]) for the remainder of their lives (~12 months). (b) Plasma DNP concentrations in 6 h fasted CRMP‐treated D2B6 and B6D2 mice. (c–j) Body weight (c–f) and body temperature (g–j) trajectories in D2B6 and B6D2 male and female mice. (K–L) 6 h FPG (K) and insulin (L) in D2B6 and B6D2 male and female mice treated for 3 months with CRMP (10 mg/[kg‐day]) or vehicle control. In all panels, data are presented as mean ± SEM. n = 4 (b), 11–29 (c‐j), 7–18 (k), and 7–11 (l) per treatment group. *p < .05 by two‐sided unpaired Student's t test compared to vehicle control (d, g–j). Abbreviations: C57BL/6J (B6); CRMP, controlled‐release mitochondrial protonophore; DBA/2J (D2); DNP, 2, 4‐dinitrophenol; FPG, fasting plasma glucose; HFD, high‐fat dietCC BY · PubMed Central
FIGURE 6 Effect of CRMP on neoplastic and non‐neoplastic disease incidence in HFD‐fed mice. Kaplan‐Meier survival curves for D2B6 males (a), B6D2 males (b), D2B6 females (c), and B6D2 females (d) fed a HFD (45%) or HFD containing CRMP (10 mg/[kg‐day]). (e–h) Heatmaps depicting frequency of neoplastic and non‐neoplastic disease incidence in mice treated as in (a–d). Mean age at necropsy: B6D2 males (35, 31 months); B6D2 females (32, 31 months); D2B6 males (30, 28 months); D2B6 females (27, 31 months). n = 30–31 per treatment group. C57BL/6J (B6); CRMP, controlled‐release mitochondrial protonophore; DBA/2J (D2); HFD, high‐fat diet
FIGURE 6 Effect of CRMP on neoplastic and non‐neoplastic disease incidence in HFD‐fed mice. Kaplan‐Meier survival curves for D2B6 males (a), B6D2 males (b), D2B6 females (c), and B6D2 females (d) fed a HFD (45%) or HFD containing CRMP (10 mg/[kg‐day]). (e–h) Heatmaps depicting frequency of neoplastic and non‐neoplastic disease incidence in mice treated as in (a–d). Mean age at necropsy: B6D2 males (35, 31 months); B6D2 females (32, 31 months); D2B6 males (30, 28 months); D2B6 females (27, 31 months). n = 30–31 per treatment group. C57BL/6J (B6); CRMP, controlled‐release mitochondrial protonophore; DBA/2J (D2); HFD, high‐fat dietCC BY · PubMed Central

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Cites

Research works printed but not linked: 67

  1. 10.1016/j.metabol.2018.12.003 · DOI
  2. 10.1096/fj.201700001R · DOI · Paper page
  3. 10.1194/jlr.RA119000586 · DOI
  4. 10.1093/gerona/glx212 · DOI
  5. 10.1159/000078349 · DOI
  6. 10.1016/j.tibs.2017.06.005 · DOI
  7. 10.1074/jbc.M408918200 · DOI
  8. 10.1093/gerona/gls332 · DOI
  9. 10.1177/019262339502300503 · DOI · Paper page
  10. 10.1016/j.mito.2020.07.007 · DOI
  11. 10.1016/S0531-5565(00)00135-2 · DOI · Paper page
  12. 10.1177/0300985811430696 · DOI
  13. 10.1111/j.1474-9726.2008.00407.x · DOI · Paper page
  14. 10.1038/nrc1408 · DOI · Paper page
  15. 10.1056/NEJMoa021423 · DOI · Paper page
  16. 10.7554/eLife.55513 · DOI
  17. 10.1021/acs.jmedchem.7b01182 · DOI
  18. 10.1155/2014/238463 · DOI · Paper page
  19. 10.1016/bs.pmbts.2016.12.015 · DOI
  20. 10.1002/mas.21381 · DOI
  21. 10.18632/aging.100067 · DOI · Paper page
  22. 10.1016/j.cmet.2005.01.005 · DOI
  23. 10.1002/hep.30097 · DOI
  24. 10.1126/scitranslmed.aay0284 · DOI · Paper page
  25. 10.1016/j.molmet.2021.101178 · DOI
  26. 10.1093/gerona/gly161 · DOI
  27. 10.1038/s41598-018-20909-w · DOI
  28. 10.1016/j.exger.2007.03.009 · DOI
  29. 10.1093/gerona/60.12.1510 · DOI · Paper page
  30. 10.1111/jgs.12876 · DOI
  31. Jeng H. A., 2015, Measurement of 8‐Oxo‐7,8‐dihydro‐2′‐deoxyguanosine in human semen and urine by isotope‐dilution liquid chromatography‐tandem mass spectrometry with on‐line solid‐phase extraction: Comparison with a commercial available enzyme‐linked immunosorbent assay, Andrology, 1, 1
  32. 10.1016/j.mad.2009.05.001 · DOI
  33. 10.1016/j.cell.2016.07.031 · DOI · Paper page
  34. 10.1016/j.cmet.2020.08.001 · DOI
  35. McCarter R. J., 1997, Physical activity as a factor in the action of dietary restriction on aging: Effects in Fischer 344 rats, Aging, 9, 73
  36. 10.1016/j.cmet.2018.08.011 · DOI
  37. 10.1073/pnas.0812484106 · DOI
  38. 10.1007/s11357-019-00062-6 · DOI
  39. 10.1038/oby.2009.477 · DOI
  40. 10.1016/j.cmet.2018.12.013 · DOI
  41. 10.1155/2016/1987960 · DOI
  42. 10.3390/nu12051416 · DOI
  43. 10.1016/j.cell.2009.12.052 · DOI · Paper page
  44. 10.1016/j.cell.2015.01.012 · DOI · Paper page
  45. 10.1016/j.cmet.2013.10.004 · DOI
  46. 10.1172/JCI86013 · DOI
  47. 10.1016/j.yjmcc.2015.04.023 · DOI
  48. 10.1016/j.cmet.2012.04.003 · DOI · Paper page
  49. 10.1016/j.bbadis.2019.165612 · DOI · Paper page
  50. 10.1016/j.ccr.2008.06.016 · DOI · Paper page
  51. 10.2147/CIA.S48918 · DOI
  52. 10.1074/jbc.M313478200 · DOI · Paper page
  53. 10.1179/135100007X162112 · DOI
  54. 10.1016/j.molmet.2018.02.010 · DOI
  55. 10.1038/nrm.2017.110 · DOI
  56. 10.4082/kjfm.19.0087 · DOI
  57. 10.1016/j.celrep.2017.05.035 · DOI
  58. 10.1038/s41467-020-15617-x · DOI
  59. 10.1152/physiolgenomics.00122.2003 · DOI · Paper page
  60. 10.1016/j.freeradbiomed.2018.06.028 · DOI
  61. 10.1126/science.aac4357 · DOI
  62. 10.1016/j.celrep.2018.06.008 · DOI
  63. 10.1016/j.heliyon.2020.e04107 · DOI
  64. 10.1056/NEJM199710023371407 · DOI
  65. 10.1111/j.0014-3820.2003.tb00356.x · DOI
  66. 10.1111/acel.13263 · DOI
  67. 10.3389/fcell.2021.656201 · DOI

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Metadata

Authors
Goedeke, L., Murt, K. N., Di Francesco, A., Camporez, J. P., Nasiri, A. R., Wang, Y., Zhang, X., Cline, G. W., de Cabo, R., & Shulman, G. I.
Affiliations
  • Department of Internal Medicine Yale School of Medicine New Haven Connecticut USA
  • Translational Gerontology Branch Intramural Research Program National Institute on Aging, NIH Baltimore Maryland USA
ORCID
Shulman, Gerald I.
Venue
Aging Cell
Publisher
Wiley
Published
2022-01-28
Volume
21
Issue
2
ISSN
  • 1474-9718
  • 1474-9726
DOI
10.1111/acel.13539
PMC
PMC8844126
Cited by
22
References
10
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK045735, R01 DK116774, R01 DK119968)
  • National Heart, Lung, and Blood Institute (K99 HL150234)

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