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Cited by 176Adipose Tissue and MetabolismMitochondrial Function and PathologyAutophagy in Disease and Therapy

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation

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Xia, Wenmin, Veeragandham, Preethi, Cao, Yu, Xu, Yayun, Rhyne, Torrey E., Qian, Jiaxin, Hung, Chao-Wei, Zhao, Peng +14 more·2024·Nature Metabolism
DOI 10.1038/s42255-024-00978-0PMC PMC10896723

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Abstract

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L , is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.

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  1. [1]Haththotuwa, R. N., Wijeyaratne, C. N., and Senarath, U. Worldwide epidemic of obesity. Obes. Obstet.10.1016/B978-0-12-817921-5.00001-1 (2020). · DOI
  2. [2]Saltiel AR Insulin resistance in the defense against obesity Cell Metab. 2012 15 798 804 10.1016/j.cmet.2012.03.001 22682220 · DOI
  3. [4]Kahn SE Hull RL Utzschneider KM Mechanisms linking obesity to insulin resistance and type 2 diabetes Nature 2006 444 840 846 10.1038/nature05482 17167471 · DOI · Paper page
  4. [5]Reilly SM Saltiel AR Adapting to obesity with adipose tissue inflammation Nat. Rev. Endocrinol. 2017 13 633 643 10.1038/nrendo.2017.90 28799554 · DOI · Paper page
  5. [6]Hotamisligil GS Inflammation and metabolic disorders Nature 2006 444 860 867 10.1038/nature05485 17167474 · DOI · Paper page
  6. [7]Kusminski CM Scherer PE Mitochondrial dysfunction in white adipose tissue Trends Endocrinol. Metab. 2012 23 435 443 10.1016/j.tem.2012.06.004 22784416 PMC3430798 · DOI
  7. [8]Rambold AS Cohen S Lippincott-Schwartz J Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics Dev. Cell 2015 32 678 692 10.1016/j.devcel.2015.01.029 25752962 PMC4375018 · DOI · Paper page
  8. [9]Eun HK Essential role of mitochondrial function in adiponectin synthesis in adipocytes Diabetes 2007 56 2973 2981 10.2337/db07-0510 17827403 · DOI · Paper page
  9. [10]Tormos KV Mitochondrial complex III ROS regulate adipocyte differentiation Cell Metab. 2011 14 537 544 10.1016/j.cmet.2011.08.007 21982713 PMC3190168 · DOI
  10. [11]Mayer J Bates MW Dickie MM Hereditary diabetes in genetically obese mice Science 1951 113 746 747 10.1126/science.113.2948.746 14854871 · DOI
  11. [12]Kahn BB Flier JS Obesity and insulin resistance J. Clin. Invest. 2000 106 473 481 10.1172/JCI10842 10953022 PMC380258 · DOI
  12. [13]Sebastián D Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis Proc. Natl Acad. Sci. USA 2012 109 5523 5528 10.1073/pnas.1108220109 22427360 PMC3325712 · DOI · Paper page
  13. [14]Kelley DE He J Menshikova EV Ritov VB Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes Diabetes 2002 51 2944 2950 10.2337/diabetes.51.10.2944 12351431 · DOI · Paper page
  14. [15]Heilbronn LK Seng KG Turner N Campbell LV Chisholm DJ Markers of mitochondrial biogenesis and metabolism are lower in overweight and obese insulin-resistant subjects J. Clin. Endocrinol. Metab. 2007 92 1467 1473 10.1210/jc.2006-2210 17244782 · DOI · Paper page
  15. [17]Lindinger PW Important mitochondrial proteins in human omental adipose tissue show reduced expression in obesity J. Proteom. 2015 124 79 87 10.1016/j.jprot.2015.03.037 25865306 · DOI
  16. [18]Pafili K Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease J. Hepatol. 2022 77 1504 1514 10.1016/j.jhep.2022.08.010 35988689 · DOI · Paper page
  17. [19]Wai T Langer T Mitochondrial dynamics and metabolic regulation Trends Endocrinol. Metab. 2016 27 105 117 10.1016/j.tem.2015.12.001 26754340 · DOI
  18. [20]Mishra P Chan DC Metabolic regulation of mitochondrial dynamics J. Cell Biol. 2016 212 379 387 10.1083/jcb.201511036 26858267 PMC4754720 · DOI
  19. [21]Inoue M Chang L Hwang J Chiang SH Saltiel AR The exocyst complex is required for targeting of Glut4 to the plasma membrane by insulin Nature 2003 422 629 633 10.1038/nature01533 12687004 · DOI
  20. [22]Chen XW Leto D Chiang SH Wang Q Saltiel AR Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c Dev. Cell 2007 13 391 404 10.1016/j.devcel.2007.07.007 17765682 · DOI
  21. [23]Nozaki S Ueda S Takenaka N Kataoka T Satoh T Role of RalA downstream of Rac1 in insulin-dependent glucose uptake in muscle cells Cell. Signal. 2012 24 2111 2117 10.1016/j.cellsig.2012.07.013 22820503 · DOI
  22. [24]Chen XW Exocyst function regulated by effector phosphorylation Nat. Cell Biol. 2011 13 580 588 10.1038/ncb2226 21516108 PMC3904505 · DOI · Paper page
  23. [25]Karunanithi S A Rab10:RalA G protein cascade regulates insulin-stimulated glucose uptake in adipocytes Mol. Biol. Cell 2014 25 3059 3069 10.1091/mbc.e14-06-1060 25103239 PMC4230594 · DOI
  24. [26]Skorobogatko Y RalA controls glucose homeostasis by regulating glucose uptake in brown fat Proc. Natl Acad. Sci. USA 2018 115 7819 7824 10.1073/pnas.1801050115 29915037 PMC6065037 · DOI · Paper page
  25. [27]Chen, Q. et al. Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control. Sci. Adv.10.1126/SCIADV.AAV4116 (2019). PMC6459767 30989113 · DOI
  26. [28]Valentine, J. M. et al. β3-Adrenergic receptor downregulation leads to adipocyte catecholamine resistance in obesity. J. Clin. Invest.10.1172/JCI153357 (2022). PMC8759781 34847077 · DOI
  27. [29]Townsend LK Wright DC Looking on the ‘brite’ side exercise-induced browning of white adipose tissue Pflug. Arch. Eur. J. Physiol. 2018 471 455 465 10.1007/s00424-018-2177-1 29982948 · DOI · Paper page
  28. [30]Ouellet V Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans J. Clin. Invest. 2012 122 545 552 10.1172/JCI60433 22269323 PMC3266793 · DOI
  29. [31]Kajimura S Saito M A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis Annu. Rev. Physiol. 2014 76 225 249 10.1146/annurev-physiol-021113-170252 24188710 PMC4090362 · DOI
  30. [32]Davis RJ Martin BR The effect of β-adrenergic agonists on the membrane potential of fat-cell mitochondria in situ Biochem. J. 1982 206 611 618 10.1042/bj2060611 7150265 PMC1158630 · DOI
  31. [33]Reilly SM Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3 Nat. Metab. 2020 2 620 634 10.1038/s42255-020-0217-6 32694788 PMC7384260 · DOI
  32. [34]Herzig S Shaw RJ AMPK: guardian of metabolism and mitochondrial homeostasis Nat. Rev. Mol. Cell Biol. 2017 19 121 135 10.1038/nrm.2017.95 28974774 PMC5780224 · DOI
  33. [35]Zhao P TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue Cell 2018 172 731 743 10.1016/j.cell.2018.01.007 29425491 PMC5808582 · DOI
  34. [36]Liesa M Shirihai OS Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure Cell Metab. 2013 17 491 506 10.1016/j.cmet.2013.03.002 23562075 PMC5967396 · DOI · Paper page
  35. [37]Wilson-Fritch L Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone J. Clin. Invest. 2004 114 1281 1289 10.1172/JCI21752 15520860 PMC524228 · DOI · Paper page
  36. [39]Seale P Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice J. Clin. Invest. 2011 121 96 105 10.1172/JCI44271 21123942 PMC3007155 · DOI
  37. [40]Chan DC Mitochondrial dynamics and its involvement in disease Annu Rev. Pathol. 2020 15 235 259 10.1146/annurev-pathmechdis-012419-032711 31585519 · DOI · Paper page
  38. [41]Song Z Chen H Fiket M Alexander C Chan DC OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L J. Cell Biol. 2007 178 749 755 10.1083/jcb.200704110 17709429 PMC2064540 · DOI
  39. [42]Mishra P Carelli V Manfredi G Chan DC Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation Cell Metab. 2014 19 630 641 10.1016/j.cmet.2014.03.011 24703695 PMC4018240 · DOI · Paper page
  40. [43]Ge, Y. et al. Two forms of opa1 cooperate to complete fusion of the mitochondrial inner-membrane. eLife10.7554/ELIFE.50973 (2020). PMC7299343 31922487
  41. [44]Chang CR Blackstone C Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology J. Biol. Chem. 2007 282 21583 21587 10.1074/jbc.C700083200 17553808 · DOI
  42. [45]Cribbs JT Strack S Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death EMBO Rep. 2007 8 939 944 10.1038/sj.embor.7401062 17721437 PMC2002551 · DOI
  43. [47]Moskalenko S The exocyst is a Ral effector complex Nat. Cell Biol. 2002 4 66 72 10.1038/ncb728 11740492 · DOI · Paper page
  44. [48]Kashatus DF RALA and RALBP1 regulate mitochondrial fission at mitosis Nat. Cell Biol. 2011 13 1108 1115 10.1038/ncb2310 21822277 PMC3167028 · DOI · Paper page
  45. [49]Xiao YX Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size J. Clin. Endocrinol. Metab. 2014 99 E209 10.1210/jc.2013-3042 24276464 PMC3913808 · DOI
  46. [50]Spiegelman BM Flier JS Obesity and the regulation of energy balance Cell 2001 104 531 543 10.1016/S0092-8674(01)00240-9 11239410 · DOI · Paper page
  47. [51]Chen Q GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins Cell. Signal. 2014 26 1636 1648 10.1016/j.cellsig.2014.04.012 24768767 · DOI
  48. [52]Marette A Regional variation in adipose tissue insulin action and GLUT4 glucose transporter expression in severely obese premenopausal women Diabetologia 1997 40 590 598 10.1007/s001250050720 9165229 · DOI
  49. [53]Carvalho E Jansson P Nagaev I Wenthzel A Smith U Insulin resistance with low cellular IRS‐1 expression is also associated with low GLUT4 expression and impaired insulin‐stimulated glucose transport 1 FASEB J. 2001 15 1101 1103 10.1096/fsb2fj000435fje 11292681 · DOI
  50. [55]Trayhurn P Wang B Wood IS Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br. J. Nutr. 2008 100 227 235 10.1017/S0007114508971282 18397542 · DOI · Paper page
  51. [57]Perry RJ Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes Cell 2015 160 745 758 10.1016/j.cell.2015.01.012 25662011 PMC4498261 · DOI · Paper page
  52. [58]Giralt M Villarroya F White, brown, beige/brite: different adipose cells for different functions? Endocrinology 2013 154 2992 3000 10.1210/en.2013-1403 23782940 · DOI
  53. [60]Forner F Proteome differences between brown and white fat mitochondria reveal specialized metabolic functions Cell Metab. 2009 10 324 335 10.1016/j.cmet.2009.08.014 19808025 · DOI
  54. [61]Banerjee R Mukherjee A Nagotu S Mitochondrial dynamics and its impact on human health and diseases: inside the DRP1 blackbox J. Mol. Med. 2021 100 1 21 10.1007/s00109-021-02150-7 34657190 · DOI
  55. [62]Jheng H-F Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle Mol. Cell. Biol. 2012 32 309 319 10.1128/MCB.05603-11 22083962 PMC3255771 · DOI · Paper page
  56. [63]Kugler BA Roux-en-Y gastric bypass surgery restores insulin-mediated glucose partitioning and mitochondrial dynamics in primary myotubes from severely obese humans Int. J. Obes. 2019 44 684 696 10.1038/s41366-019-0469-y PMC7050434 31624314 · DOI
  57. [64]Gundersen AE Altered mitochondrial network morphology and regulatory proteins in mitochondrial quality control in myotubes from severely obese humans with or without type 2 diabetes Appl. Physiol. Nutr. Metab. 2020 45 283 293 10.1139/apnm-2019-0208 31356754 PMC12548805 · DOI
  58. [65]Wikstrom JD Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure EMBO J. 2014 33 418 24431221 PMC3983686
  59. [66]Li X Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue FASEB J. 2020 34 8265 10.1096/fj.201903100RR 32294302 PMC7336545 · DOI
  60. [67]Kugler BA Pharmacological inhibition of dynamin-related protein 1 attenuates skeletal muscle insulin resistance in obesity Physiol. Rep. 2021 9 e14808 10.14814/phy2.14808 33904649 PMC8077121 · DOI
  61. [68]Finocchietto P Inhibition of mitochondrial fission by Drp-1 blockade by short-term leptin and Mdivi-1 treatment improves white adipose tissue abnormalities in obesity and diabetes Pharmacol. Res. 2022 178 106028 10.1016/j.phrs.2021.106028 34896541 · DOI
  62. [69]Wang L Disruption of mitochondrial fission in the liver protects mice from diet-induced obesity and metabolic deterioration Diabetologia 2015 58 2371 2380 10.1007/s00125-015-3704-7 26233250 · DOI
  63. [70]Mooli, R. G. R., Mukhi, D., Chen, Z., Buckner, N. & Ramakrishnan, S. K. An indispensable role for dynamin-related protein 1 in beige and brown adipogenesis. J. Cell Sci. 10.1242/jcs.247593 (2020). PMC10390025 32843579 · DOI
  64. [71]Valera-Alberni, M. et al. Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation. Cell Rep.10.1016/J.CELREP.2021.109565 (2021). PMC8411118 34433037 · DOI
  65. [72]Kleele T Distinct fission signatures predict mitochondrial degradation or biogenesis Nature 2021 593 435 439 10.1038/s41586-021-03510-6 33953403 · DOI · Paper page
  66. [73]Adachi Y Drp1 tubulates the ER in a GTPase-Independent manner Mol. Cell 2020 80 621 632 10.1016/j.molcel.2020.10.013 33152269 PMC7680448 · DOI
  67. [74]Czech MP Insulin action and resistance in obesity and type 2 diabetes Nat. Med. 2017 23 804 814 10.1038/nm.4350 28697184 PMC6048953 · DOI · Paper page
  68. [75]Huang J NBR1 is a critical step in the repression of thermogenesis of p62-deficient adipocytes through PPARγ Nat. Commun. 2021 12 2876 10.1038/s41467-021-23085-0 34001883 PMC8129077 · DOI
  69. [76]Schweiger M Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice Nat. Commun. 2017 8 14859 10.1038/ncomms14859 28327588 PMC5364409 · DOI
  70. [77]Arner E Adipose tissue MicroRNAs as regulators of CCL2 production in human obesity Diabetes 2012 61 1986 1993 10.2337/db11-1508 22688341 PMC3402332 · DOI
  71. [78]Civelek M Genetic regulation of adipose gene expression and cardio-metabolic traits Am. J. Hum. Genet. 2017 100 428 443 10.1016/j.ajhg.2017.01.027 28257690 PMC5339333 · DOI
  72. [80]Mina AI CalR: A web-based analysis tool for indirect calorimetry experiments Cell Metab. 2018 28 656 666 10.1016/j.cmet.2018.06.019 30017358 PMC6170709 · DOI · Paper page
  73. [81]Chen BC Lattice light-sheet microscopy: Imaging molecules to embryos at high spatiotemporal resolution Science 2014 346 1257998 10.1126/science.1257998 25342811 PMC4336192 · DOI
  74. [82]Wang Z MitoTNT: mitochondrial temporal network tracking for 4D live-cell fluorescence microscopy data PLoS Comput. Biol. 2023 19 1 24 10.1371/journal.pcbi.1011060 PMC10184899 37083820 · DOI

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Authors
Xia, W., Veeragandham, P., Cao, Y., Xu, Y., Rhyne, T. E., Qian, J., Hung, C.-W., Zhao, P., Jones, Y., Gao, H., Liddle, C., Yu, R. T., Downes, M., Evans, R. M., Rydén, M., Wabitsch, M., Wang, Z., Hakozaki, H., Schöneberg, J., Reilly, S. M., Huang, J., & Saltiel, A. R.
Affiliations
  • University of California San Diego (US)
  • The University of Texas at San Antonio Health Science Center (US)
  • Karolinska Institutet (SE)
  • The University of Sydney (AU)
  • Salk Institute for Biological Studies (US)
  • Karolinska University Hospital (SE)
  • University Hospital Ulm (DE)
Corresponding author
Saltiel, Alan R.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2024-01-29
Volume
6
Issue
2
Pages
273-289
ISSN
2522-5812 (ISSN-L)
DOI
10.1038/s42255-024-00978-0
PMC
PMC10896723
OpenAlex
W4391322596
Cited by
176
References
8
Citations by year
2026: 77 · 2025: 66 · 2024: 32 · 2023: 1
FWCI
45.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Metabolism (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491, R01DK122804, R01DK124496, R01DK125820, R01DK128796, R00HL143277, R01DK126944)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
obesity, mitochondrial fragmentation, white adipocytes, RalA, Drp1, mitochondrial fission, high-fat diet, fatty acid oxidation, energy expenditure, insulin resistance, mitochondrial dynamics, weight gain

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