Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity

Jonathan R. Brestoff; Craig B. Wilen; John R. Moley; Yongjia Li; Wei Zou; Nicole P. Malvin; Marina N. Rowen; Brian T. Saunders; Hongming Ma; Madison R. Mack; Barry L. Hykes; Dale R. Balce; Anthony Orvedahl; Jesse W. Williams; Nidhi Rohatgi; Xiaoyan Wang; Michael R. McAllaster; Scott A. Handley; Brian S. Kim; John G. Doench; Bernd H. Zinselmeyer; Michael S. Diamond; Herbert W. Virgin; Andrew E. Gelman; Steven L. Teitelbaum

doi:10.1016/j.cmet.2020.11.008

Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity

Jonathan R. Brestoff, Craig B. Wilen, John R. Moley, Yongjia Li, Wei Zou, Nicole P. Malvin, Marina N. Rowen, Brian T. Saunders, Hongming Ma, Madison R. Mack, Barry L. Hykes, Dale R. Balce, Anthony Orvedahl, Jesse W. Williams, Nidhi Rohatgi, Xiaoyan Wang, Michael R. McAllaster, Scott A. Handley, Brian S. Kim, John G. DoenchBernd H. Zinselmeyer, Michael S. Diamond, Herbert W. Virgin, Andrew E. Gelman, Steven L. Teitelbaum

Research output: Contribution to journal › Article › peer-review

170 Scopus citations

Abstract

Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.

Original language	English (US)
Pages (from-to)	270-282.e8
Journal	Cell Metabolism
Volume	33
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2020.11.008
State	Published - Feb 2 2021
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) R01-DK111389 , NIH Merit award R37-AR046523 , Shriner’s Hospital for Children grant # 85400 , and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director’s Early Independence Award ( DP5 OD028125 ), the Burroughs Wellcome Fund (CAMS 1019648 ), and Children’s Discovery Institute ( MI-F-2019-795 ) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support.

Funding Information:
This work was supported by National Institutes of Health (NIH) R01-DK111389, NIH Merit award R37-AR046523, Shriner's Hospital for Children grant #85400, and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director's Early Independence Award (DP5 OD028125), the Burroughs Wellcome Fund (CAMS 1019648), and Children's Discovery Institute (MI-F-2019-795) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support. J.R.B. C.B.W. J.R.M. M.N.R. N.P.M. Y.L. W.Z. H.M. B.T.S. M.R.M. B.L.S. D.R.B. A.O. and J.W.W. performed experiments. J.R.B. C.B.W. J.R.M. H.M. D.B. A.O. B.H.Z. S.A.H. B.S.K. J.D. G.J.R. M.S.D. H.W.V. A.E.G. and S.L.T. designed the project. J.R.B. C.B.W. J.R.M. Y.L. B.T.S. M.R.M. B.L.H. Jr. W.Z. N.R. X.W. B.H.Z. and J.W.W. analyzed the data. J.R.B. wrote the paper. All authors read, edited, and approved the manuscript. D.R.B. and H.W.V. are employees of J. Virol. Biotechnol. a for-profit institution. H.W.V. is a founder of PierenianDx and Casma Therapeutics. M.S.D. is a consultant for Inbios and on the Scientific Advisory Board of Moderna. B.S.K. has served as a consultant for AbbVie, Inc. Concert Pharmaceuticals, Incyte Corporation, Menlo Therapeutics, and Pfizer, Inc; has participated on the advisory board for Celgene Corporation, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Inc. Sanofi, and Theravance Pharmaceuticals; is a stockholder of Gilead Sciences, Inc. and Mallinckrodt Pharmaceuticals; and is a Founder and Chief Scientific Officer of Nuogen Pharma, Inc. The other authors declare no competing interests.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

beige adipose tissue
brown adipose tissue
horizontal mitochondria transfer
immunometabolism
intercellular mitochondria transfer
macrophage
metabolism
mitochondria
obesity
white adipose tissue

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2020.11.008

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Brestoff, J. R., Wilen, C. B., Moley, J. R., Li, Y., Zou, W., Malvin, N. P., Rowen, M. N., Saunders, B. T., Ma, H., Mack, M. R., Hykes, B. L., Balce, D. R., Orvedahl, A., Williams, J. W., Rohatgi, N., Wang, X., McAllaster, M. R., Handley, S. A., Kim, B. S., ... Teitelbaum, S. L. (2021). Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity. Cell Metabolism, 33(2), 270-282.e8. https://doi.org/10.1016/j.cmet.2020.11.008

Brestoff, JR, Wilen, CB, Moley, JR, Li, Y, Zou, W, Malvin, NP, Rowen, MN, Saunders, BT, Ma, H, Mack, MR, Hykes, BL, Balce, DR, Orvedahl, A, Williams, JW, Rohatgi, N, Wang, X, McAllaster, MR, Handley, SA, Kim, BS, Doench, JG, Zinselmeyer, BH, Diamond, MS, Virgin, HW, Gelman, AE & Teitelbaum, SL 2021, 'Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity', Cell Metabolism, vol. 33, no. 2, pp. 270-282.e8. https://doi.org/10.1016/j.cmet.2020.11.008

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title = "Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity",

abstract = "Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.",

keywords = "beige adipose tissue, brown adipose tissue, horizontal mitochondria transfer, immunometabolism, intercellular mitochondria transfer, macrophage, metabolism, mitochondria, obesity, white adipose tissue",

author = "Brestoff, {Jonathan R.} and Wilen, {Craig B.} and Moley, {John R.} and Yongjia Li and Wei Zou and Malvin, {Nicole P.} and Rowen, {Marina N.} and Saunders, {Brian T.} and Hongming Ma and Mack, {Madison R.} and Hykes, {Barry L.} and Balce, {Dale R.} and Anthony Orvedahl and Williams, {Jesse W.} and Nidhi Rohatgi and Xiaoyan Wang and McAllaster, {Michael R.} and Handley, {Scott A.} and Kim, {Brian S.} and Doench, {John G.} and Zinselmeyer, {Bernd H.} and Diamond, {Michael S.} and Virgin, {Herbert W.} and Gelman, {Andrew E.} and Teitelbaum, {Steven L.}",

note = "Funding Information: This work was supported by National Institutes of Health (NIH) R01-DK111389 , NIH Merit award R37-AR046523 , Shriner{\textquoteright}s Hospital for Children grant # 85400 , and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director{\textquoteright}s Early Independence Award ( DP5 OD028125 ), the Burroughs Wellcome Fund (CAMS 1019648 ), and Children{\textquoteright}s Discovery Institute ( MI-F-2019-795 ) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support. Funding Information: This work was supported by National Institutes of Health (NIH) R01-DK111389, NIH Merit award R37-AR046523, Shriner's Hospital for Children grant #85400, and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director's Early Independence Award (DP5 OD028125), the Burroughs Wellcome Fund (CAMS 1019648), and Children's Discovery Institute (MI-F-2019-795) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support. J.R.B. C.B.W. J.R.M. M.N.R. N.P.M. Y.L. W.Z. H.M. B.T.S. M.R.M. B.L.S. D.R.B. A.O. and J.W.W. performed experiments. J.R.B. C.B.W. J.R.M. H.M. D.B. A.O. B.H.Z. S.A.H. B.S.K. J.D. G.J.R. M.S.D. H.W.V. A.E.G. and S.L.T. designed the project. J.R.B. C.B.W. J.R.M. Y.L. B.T.S. M.R.M. B.L.H. Jr. W.Z. N.R. X.W. B.H.Z. and J.W.W. analyzed the data. J.R.B. wrote the paper. All authors read, edited, and approved the manuscript. D.R.B. and H.W.V. are employees of J. Virol. Biotechnol. a for-profit institution. H.W.V. is a founder of PierenianDx and Casma Therapeutics. M.S.D. is a consultant for Inbios and on the Scientific Advisory Board of Moderna. B.S.K. has served as a consultant for AbbVie, Inc. Concert Pharmaceuticals, Incyte Corporation, Menlo Therapeutics, and Pfizer, Inc; has participated on the advisory board for Celgene Corporation, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Inc. Sanofi, and Theravance Pharmaceuticals; is a stockholder of Gilead Sciences, Inc. and Mallinckrodt Pharmaceuticals; and is a Founder and Chief Scientific Officer of Nuogen Pharma, Inc. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2021",

month = feb,

day = "2",

doi = "10.1016/j.cmet.2020.11.008",

language = "English (US)",

volume = "33",

pages = "270--282.e8",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "2",

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TY - JOUR

T1 - Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity

AU - Brestoff, Jonathan R.

AU - Wilen, Craig B.

AU - Moley, John R.

AU - Li, Yongjia

AU - Zou, Wei

AU - Malvin, Nicole P.

AU - Rowen, Marina N.

AU - Saunders, Brian T.

AU - Ma, Hongming

AU - Mack, Madison R.

AU - Hykes, Barry L.

AU - Balce, Dale R.

AU - Orvedahl, Anthony

AU - Williams, Jesse W.

AU - Rohatgi, Nidhi

AU - Wang, Xiaoyan

AU - McAllaster, Michael R.

AU - Handley, Scott A.

AU - Kim, Brian S.

AU - Doench, John G.

AU - Zinselmeyer, Bernd H.

AU - Diamond, Michael S.

AU - Virgin, Herbert W.

AU - Gelman, Andrew E.

AU - Teitelbaum, Steven L.

N1 - Funding Information: This work was supported by National Institutes of Health (NIH) R01-DK111389 , NIH Merit award R37-AR046523 , Shriner’s Hospital for Children grant # 85400 , and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director’s Early Independence Award ( DP5 OD028125 ), the Burroughs Wellcome Fund (CAMS 1019648 ), and Children’s Discovery Institute ( MI-F-2019-795 ) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support. Funding Information: This work was supported by National Institutes of Health (NIH) R01-DK111389, NIH Merit award R37-AR046523, Shriner's Hospital for Children grant #85400, and a grant from Siteman Cancer Center to S.L.T. Additional funding was provided by the NIH Director's Early Independence Award (DP5 OD028125), the Burroughs Wellcome Fund (CAMS 1019648), and Children's Discovery Institute (MI-F-2019-795) to J.R.B. Support was also provided by NIH R01-AI123348 (M.S.D.), U19-AI142784 (H.W.V.), K08-AR065577 (B.S.K.), R01-AR070116 (B.S.K.), Doris Duke Charitable Foundation (B.S.K.), Celgene Corporation (B.S.K.), Leo Pharma (B.S.K.), and K99-HL138163 (J.W.W.). The Genome Technology Access Center (GTAC) is partially supported by NCI Cancer Center Support grant P30 CA91842 to Siteman Cancer Center, ICTS/CTSA grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. We thank D. Brinja and E. Lantelme at the flow cytometry and cell sorting Core and E. Tycksen at GTAC at Washington University School of Medicine for their technical support. J.R.B. C.B.W. J.R.M. M.N.R. N.P.M. Y.L. W.Z. H.M. B.T.S. M.R.M. B.L.S. D.R.B. A.O. and J.W.W. performed experiments. J.R.B. C.B.W. J.R.M. H.M. D.B. A.O. B.H.Z. S.A.H. B.S.K. J.D. G.J.R. M.S.D. H.W.V. A.E.G. and S.L.T. designed the project. J.R.B. C.B.W. J.R.M. Y.L. B.T.S. M.R.M. B.L.H. Jr. W.Z. N.R. X.W. B.H.Z. and J.W.W. analyzed the data. J.R.B. wrote the paper. All authors read, edited, and approved the manuscript. D.R.B. and H.W.V. are employees of J. Virol. Biotechnol. a for-profit institution. H.W.V. is a founder of PierenianDx and Casma Therapeutics. M.S.D. is a consultant for Inbios and on the Scientific Advisory Board of Moderna. B.S.K. has served as a consultant for AbbVie, Inc. Concert Pharmaceuticals, Incyte Corporation, Menlo Therapeutics, and Pfizer, Inc; has participated on the advisory board for Celgene Corporation, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Inc. Sanofi, and Theravance Pharmaceuticals; is a stockholder of Gilead Sciences, Inc. and Mallinckrodt Pharmaceuticals; and is a Founder and Chief Scientific Officer of Nuogen Pharma, Inc. The other authors declare no competing interests. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2021/2/2

Y1 - 2021/2/2

N2 - Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.

AB - Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity.

KW - beige adipose tissue

KW - brown adipose tissue

KW - horizontal mitochondria transfer

KW - immunometabolism

KW - intercellular mitochondria transfer

KW - macrophage

KW - metabolism

KW - mitochondria

KW - obesity

KW - white adipose tissue

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U2 - 10.1016/j.cmet.2020.11.008

DO - 10.1016/j.cmet.2020.11.008

M3 - Article

C2 - 33278339

AN - SCOPUS:85097880087

SN - 1550-4131

VL - 33

SP - 270-282.e8

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

Intercellular Mitochondria Transfer to Macrophages Regulates White Adipose Tissue Homeostasis and Is Impaired in Obesity

Abstract

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Keywords

UN SDGs

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