Original Paper | Published:

Loss of BIM increases mitochondrial oxygen consumption and lipid oxidation, reduces adiposity and improves insulin sensitivity in mice

Cell Death and Differentiation volume 25, pages 217225 (2018) | Download Citation

Edited by L Scorrano

Abstract

BCL-2 proteins are known to engage each other to determine the fate of a cell after a death stimulus. However, their evolutionary conservation and the many other reported binding partners suggest an additional function not directly linked to apoptosis regulation. To identify such a function, we studied mice lacking the BH3-only protein BIM. BIM−/− cells had a higher mitochondrial oxygen consumption rate that was associated with higher mitochondrial complex IV activity. The consequences of increased oxygen consumption in BIM−/− mice were significantly lower body weights, reduced adiposity and lower hepatic lipid content. Consistent with reduced adiposity, BIM−/− mice had lower fasting blood glucose, improved insulin sensitivity and hepatic insulin signalling. Lipid oxidation was increased in BIM−/− mice, suggesting a mechanism for their metabolic phenotype. Our data suggest a role for BIM in regulating mitochondrial bioenergetics and metabolism and support the idea that regulation of metabolism and cell death are connected.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , . The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 92–103.

  2. 2.

    , , , , , et al. The oxidative phosphorylation system in mammalian mitochondria. Adv Exp Med Biol 2012; 942: 3–37.

  3. 3.

    , , , . Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 2014; 15: 49–63.

  4. 4.

    , , . BH3-only proteins and their roles in programmed cell death. Oncogene 2008; 27: S128–S136.

  5. 5.

    , , , , , et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286: 1735–1738.

  6. 6.

    , , , , , et al. The BH3-only protein Puma plays an essential role in cytokine deprivation induced apoptosis of mast cells. Blood 2007; 110: 3209–3217.

  7. 7.

    , , , , , et al. BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 2005; 106: 4131–4138.

  8. 8.

    , , , , , et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 2007; 129: 1337–1349.

  9. 9.

    , , , , , . The pro-apoptotic BH3-only protein Bim interacts with components of the translocase of the outer mitochondrial membrane (TOM). PLoS One 2015; 10: e0123341.

  10. 10.

    , , , , , et al. Constitutive association of the proapoptotic protein Bim with Bcl-2-related proteins on mitochondria in T cells. Proc Natl Acad Sci USA 2004; 101: 7681–7686.

  11. 11.

    , , , , , et al. BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals. Cell Death Differ 2008; 15: 1063–1072.

  12. 12.

    , , , , et al. Bcl-xL increases mitochondrial fission, fusion, and biomass in neurons. J Cell Biol 2009; 184: 707–719.

  13. 13.

    , , , , , et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nat Cell Biol 2012; 14: 575–583.

  14. 14.

    , . A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 2010; 33: 469–477.

  15. 15.

    , . The Randle cycle revisited: a new head for an old hat. Am J Physiol Endocrinol Metab 2009; 297: E578–E591.

  16. 16.

    . The impact of pharmacotherapy on weight management in type 2 diabetes. Int J Obes Relat Metab Disord 1999; 23: S12–S17.

  17. 17.

    , , , , , et al. Differential effect of inbred mouse strain (C57BL/6, DBA/2, 129T2) on insulin secretory function in response to a high fat diet. J Endocrinol 2005; 187: 45–53.

  18. 18.

    , , , , , et al. Liver Patt1 deficiency protects male mice from age-associated but not high-fat diet-induced hepatic steatosis. J Lipid Res 2012; 53: 358–367.

  19. 19.

    , . Mechanisms for insulin resistance: common threads and missing links. Cell 2012; 148: 852–871.

  20. 20.

    , , , , , et al. Metabolic remodeling of white adipose tissue in obesity. Am J Physiol Endocrinol Metab 2014; 307: E262–E277.

  21. 21.

    , , , , , et al. Improved insulin sensitivity associated with reduced mitochondrial complex IV assembly and activity. FASEB J 2013; 27: 1371–1380.

  22. 22.

    , , , , , et al. Defects in the Bcl-2-regulated apoptotic pathway lead to preferential increase of CD25 low Foxp3+ anergic CD4+ T cells. J Immunol 2011; 187: 1566–1577.

  23. 23.

    , , , , , . FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J Cell Sci 2012; 125: 1191–1203.

  24. 24.

    , , , , , et al. Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs. Blood 2009; 114: 5342–5351.

  25. 25.

    , , , . Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci USA 2004; 101: 6164–6169.

  26. 26.

    , , , , , et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nat Cell Biol 2011; 13: 1224–1233.

  27. 27.

    , , , , , et al. Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential. J Cell Biol 2011; 195: 263–276.

  28. 28.

    , . Involvement of cytochrome c oxidase subunits Va and Vb in the regulation of cancer cell metabolism by Bcl-2. Cell Death Differ 2010; 17: 408–420.

  29. 29.

    , , , , , et al. Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. Diabetes 2016; 65: 3200–3211.

  30. 30.

    , , , , , et al. Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. Am J Hum Genet 2012; 90: 410–425.

  31. 31.

    , , , , , et al. New genetic loci link adipose and insulin biology to body fat distribution. Nature 2015; 518: 187–196.

  32. 32.

    , , , , , et al. Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets. Cell Death Differ 2007; 14: 128–136.

  33. 33.

    , , , , , et al. Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab 2014; 19: 272–284.

  34. 34.

    , , , , , et al. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol 2012; 32: 2570–2584.

  35. 35.

    , , , , , et al. p53-upregulated-modulator-of-apoptosis (PUMA) deficiency affects food intake but does not impact on body weight or glucose homeostasis in diet-induced obesity. Sci Rep 2016; 6: 23802.

  36. 36.

    , , . AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol 2013; 366: 135–151.

  37. 37.

    , , , , , et al. AMP kinase-mediated activation of the BH3-only protein Bim couples energy depletion to stress-induced apoptosis. J Cell Biol 2010; 189: 83–94.

  38. 38.

    , , , , , et al. AMP-activated protein kinase can induce apoptosis of insulin-producing MIN6 cells through stimulation of c-Jun-N-terminal kinase. J Mol Endocrinol 2003; 30: 151–161.

  39. 39.

    , , , , , et al. Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells. FEBS Lett 2002; 526: 38–42.

  40. 40.

    , , , , , et al. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 2013; 123: 4888–4899.

  41. 41.

    , , , , , et al. Imeglimin normalizes glucose tolerance and insulin sensitivity and improves mitochondrial function in liver of a high-fat, high-sucrose diet mice model. Diabetes 2015; 64: 2254–2264.

  42. 42.

    , , , , , et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19: 1649–1654.

  43. 43.

    , , , , , et al. Metformin improves healthspan and lifespan in mice. Nat Commun 2013; 4: 2192.

  44. 44.

    , , , , , et al. Disruption of the class IIa HDAC Corepressor complex increases energy expenditure and lipid oxidation. Cell Rep 2016; 16: 2802–2810.

  45. 45.

    , , , , , et al. Comparison of insulin secretory function in two mouse models with different susceptibility to beta-cell failure. Endocrinology 2002; 143: 2085–2092.

  46. 46.

    , , , , , et al. Perforin and Fas induced by IFNgamma and TNFalpha mediate beta cell death by OT-I CTL. Int Immunol 2006; 18: 837–846.

  47. 47.

    , , , , , et al. Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. Cell Metab 2014; 20: 85–102.

  48. 48.

    , , . Blue native PAGE. Nat Protoc 2006; 1: 418–428.

  49. 49.

    , , , . Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action. Mol Metab 2014; 3: 408–418.

  50. 50.

    , . Biochemical analyses of the electron transport chain complexes by spectrophotometry. Methods Mol Biol 2012; 837: 49–62.

  51. 51.

    , , , , . Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Nat Protoc 2013; 8: 1149–1154.

  52. 52.

    , , , , , et al. Impaired lactation in mice expressing dominant-negative FADD in mammary epithelium. Dev Dyn 2009; 238: 1010–1016.

Download references

Acknowledgements

We thank Lorraine Elkerbout, Stacey Fynch, William Stanley, Jasmine McLeod, Lara Yachou-Wos, Sam Thorburn, Eva Orlowski (all St Vincent’s Institute), Adrienne Laskowski (Murdoch Childrens Research Institute), Philippe Bouillet, Andreas Strasser, Lorraine O’Reilly, Marco Herold, Margs Brennan, David Huang, David Segal (The Walter and Eliza Hall Institute), Sara Ellis, Jill Danne and Chad Johnson (Peter MacCallum Cancer Centre), Greg Steinberg (McMaster University, Canada) and Sof Andrikopoulos (University of Melbourne) for experimental advice, technical assistance, reagents and critical reading of the manuscript. This work was funded by a National Health and Medical Research Council of Australia (NHMRC) Project grant, a NHMRC and Juvenile Diabetes Research Foundation joint special programme grant, and fellowships from the NHMRC. This work received support from the Operational Infrastructure Support Scheme of the Government of Victoria.

Author contributions

JAW, SG, CT, ENG, AEF, TC, JG, EGP, DS, CV, and CS performed experiments, analysed data and revised the manuscript. JAW, SG, BK, TWHK, SLM, and HET designed the study and wrote the manuscript. MTR, DRT, and BEK contributed to conception, design and interpretation of this work, provided essential reagents and critically revised the manuscript.

Author information

Author notes

    • Jibran A Wali

    Present address: Charles Perkins Centre, University of Sydney, Camperdown, NSW 2006, Australia

Affiliations

  1. St. Vincent’s Institute, Fitzroy, VIC 3065, Australia

    • Jibran A Wali
    • , Sandra Galic
    • , Christina YR Tan
    • , Esteban N Gurzov
    • , Jingjing Ge
    • , Evan G Pappas
    • , L Chitra Varanasi
    • , Claudia Selck
    • , Bruce E Kemp
    • , Balasubramanian Krishnamurthy
    • , Thomas WH Kay
    •  & Helen E Thomas
  2. The University of Melbourne, Department of Medicine, St. Vincent’s Hospital, Fitzroy, VIC 3065, Australia

    • Jibran A Wali
    • , Jingjing Ge
    • , Claudia Selck
    • , Bruce E Kemp
    • , Balasubramanian Krishnamurthy
    • , Thomas WH Kay
    •  & Helen E Thomas
  3. Murdoch Childrens Research Institute and The University of Melbourne Department of Paediatrics, Royal Childrens Hospital, Parkville, VIC 3052, Australia

    • Ann E Frazier
    •  & David R Thorburn
  4. Metabolic Reprogramming Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC 3216, Australia

    • Timothy Connor
    •  & Sean L McGee
  5. Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia

    • David Stroud
    •  & Michael T Ryan
  6. Victorian Clinical Genetics Services, Royal Childrens Hospital, Parkville, VIC 3052, Australia

    • David R Thorburn

Authors

  1. Search for Jibran A Wali in:

  2. Search for Sandra Galic in:

  3. Search for Christina YR Tan in:

  4. Search for Esteban N Gurzov in:

  5. Search for Ann E Frazier in:

  6. Search for Timothy Connor in:

  7. Search for Jingjing Ge in:

  8. Search for Evan G Pappas in:

  9. Search for David Stroud in:

  10. Search for L Chitra Varanasi in:

  11. Search for Claudia Selck in:

  12. Search for Michael T Ryan in:

  13. Search for David R Thorburn in:

  14. Search for Bruce E Kemp in:

  15. Search for Balasubramanian Krishnamurthy in:

  16. Search for Thomas WH Kay in:

  17. Search for Sean L McGee in:

  18. Search for Helen E Thomas in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Helen E Thomas.

Supplementary information

Word documents

  1. 1.

    Supplementary Figures

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/cdd.2017.168

Supplementary Information accompanies this paper on Cell Death and Differentiation website (http://www.nature.com/cdd)