Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Olivia Sveidahl Johansen; Tao Ma; Jakob Bondo Hansen; Lasse Kruse Markussen; Renate Schreiber; Laia Reverte-Salisa; Hua Dong; Dan Ploug Christensen; Wenfei Sun; Thorsten Gnad; Iuliia Karavaeva; Thomas Svava Nielsen; Sander Kooijman; Cheryl Cero; Oksana Dmytriyeva; Yachen Shen; Maria Razzoli; Shannon L. O'Brien; Eline N. Kuipers; Carsten Haagen Nielsen; William Orchard; Nienke Willemsen; Naja Zenius Jespersen; Morten Lundh; Elahu Gosney Sustarsic; Cecilie Mørch Hallgren; Mikkel Frost; Seth McGonigle; Marie Sophie Isidor; Christa Broholm; Oluf Pedersen; Jacob Bo Hansen; Niels Grarup; Torben Hansen; Andreas Kjær; James G. Granneman; M. Madan Babu; Davide Calebiro; Søren Nielsen; Mikael Rydén; Raymond Soccio; Patrick C.N. Rensen; Jonas Thue Treebak; Thue Walter Schwartz; Brice Emanuelli; Alessandro Bartolomucci; Alexander Pfeifer; Rudolf Zechner; Camilla Scheele; Susanne Mandrup; Zachary Gerhart-Hines

doi:10.1016/j.cell.2021.04.037

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

Olivia Sveidahl Johansen, Tao Ma, Jakob Bondo Hansen, Lasse Kruse Markussen, Renate Schreiber, Laia Reverte-Salisa, Hua Dong, Dan Ploug Christensen, Wenfei Sun, Thorsten Gnad, Iuliia Karavaeva, Thomas Svava Nielsen, Sander Kooijman, Cheryl Cero, Oksana Dmytriyeva, Yachen Shen, Maria Razzoli, Shannon L. O'Brien, Eline N. Kuipers, Carsten Haagen NielsenWilliam Orchard, Nienke Willemsen, Naja Zenius Jespersen, Morten Lundh, Elahu Gosney Sustarsic, Cecilie Mørch Hallgren, Mikkel Frost, Seth McGonigle, Marie Sophie Isidor, Christa Broholm, Oluf Pedersen, Jacob Bo Hansen, Niels Grarup, Torben Hansen, Andreas Kjær, James G. Granneman, M. Madan Babu, Davide Calebiro, Søren Nielsen, Mikael Rydén, Raymond Soccio, Patrick C.N. Rensen, Jonas Thue Treebak, Thue Walter Schwartz, Brice Emanuelli, Alessandro Bartolomucci, Alexander Pfeifer, Rudolf Zechner, Camilla Scheele, Susanne Mandrup, Zachary Gerhart-Hines

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

78 Scopus citations

Abstract

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Original language	English (US)
Pages (from-to)	3502-3518.e33
Journal	Cell
Volume	184
Issue number	13
DOIs	https://doi.org/10.1016/j.cell.2021.04.037
State	Published - Jun 24 2021

Bibliographical note

Funding Information:
We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the ?-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. This work was supported by the NIH, National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496, DK117504, and R56DK118150 to A.B.), the Austrian Science Fund (FWF) (F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project ?Generating the best evidence-based pharmaceutical targets for atherosclerosis? (CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling (ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G. 335447717/SFB1328 and 290847636/FOR2372 to A.P. and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406, grant ID PD007-18). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (https://cbmr.ku.dk/). D.C. is supported by a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z). Conceptualization, Z.G.-H. O.S.J. T.M. and Jakob Bondo Hansen; investigation, Z.G.-H. O.S.J. T.M. Jakob Bondo Hansen, L.K.M. R. Schreiber, L.R.-S. H.D. D.P.C. W.S. T.G. I.K. T.S.N. S.K. C.C. O.D. Y.S. M.R. S.L.O. E.N.K. C.H.N. W.O. N.W. N.Z.J. M.L. E.G.S. C.M.H. M.F. S. McGonigle, M.S.I. C.B. O.P. Jacob Bo Hansen, N.G. T.H. A.K. J.G.G. M.M.B. D.C. S.N. M.R. R. Soccio, P.C.N.R. J.T.T. T.W.S. B.E. A.B. A.P. R.Z. C.S. and S. Mandrup; writing ? original draft, Z.G.-H. and O.S.J.; writing ? review & editing, Z.G.-H. O.S.J. and T.M.; visualization, O.S.J. O.S.J. Jakob Bondo Hansen, D.P.C. T.W.S. and Z.G.-H. work or have worked, in some capacity, for Embark Biotech ApS, a company developing therapeutics for the treatment of diabetes and obesity. All other authors declare no competing interests associated with this manuscript.

Funding Information:
We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the β-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . This work was supported by the NIH , National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496 , DK117504 , and R56DK118150 to A.B.), the Austrian Science Fund (FWF) ( F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” ( CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling ( ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G., 335447717/SFB1328 and 290847636/FOR2372 to A.P., and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406 , grant ID PD007-18 ). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org ). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045 ). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation ( DNRF55 ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( https://cbmr.ku.dk/ ). D.C. is supported by a Wellcome Trust Senior Research Fellowship ( 212313/Z/18/Z ).

Publisher Copyright:
© 2021 The Author(s)

Keywords

adrenergic receptor
brown adipose tissue
constitutively active
energy expenditure
G protein-coupled receptor
GPCR
GPR3
lipolysis
thermogenesis
transcription

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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

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10.1016/j.cell.2021.04.037

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Sveidahl Johansen, O., Ma, T., Hansen, J. B., Markussen, L. K., Schreiber, R., Reverte-Salisa, L., Dong, H., Christensen, D. P., Sun, W., Gnad, T., Karavaeva, I., Nielsen, T. S., Kooijman, S., Cero, C., Dmytriyeva, O., Shen, Y., Razzoli, M., O'Brien, S. L., Kuipers, E. N., ... Gerhart-Hines, Z. (2021). Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis. Cell, 184(13), 3502-3518.e33. https://doi.org/10.1016/j.cell.2021.04.037

Sveidahl Johansen, O, Ma, T, Hansen, JB, Markussen, LK, Schreiber, R, Reverte-Salisa, L, Dong, H, Christensen, DP, Sun, W, Gnad, T, Karavaeva, I, Nielsen, TS, Kooijman, S, Cero, C, Dmytriyeva, O, Shen, Y, Razzoli, M, O'Brien, SL, Kuipers, EN, Nielsen, CH, Orchard, W, Willemsen, N, Jespersen, NZ, Lundh, M, Sustarsic, EG, Hallgren, CM, Frost, M, McGonigle, S, Isidor, MS, Broholm, C, Pedersen, O, Hansen, JB, Grarup, N, Hansen, T, Kjær, A, Granneman, JG, Babu, MM, Calebiro, D, Nielsen, S, Rydén, M, Soccio, R, Rensen, PCN, Treebak, JT, Schwartz, TW, Emanuelli, B, Bartolomucci, A, Pfeifer, A, Zechner, R, Scheele, C, Mandrup, S & Gerhart-Hines, Z 2021, 'Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis', Cell, vol. 184, no. 13, pp. 3502-3518.e33. https://doi.org/10.1016/j.cell.2021.04.037

@article{6421e2dfe55140a396b904df983855f2,

title = "Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis",

abstract = "Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.",

keywords = "adrenergic receptor, brown adipose tissue, constitutively active, energy expenditure, G protein-coupled receptor, GPCR, GPR3, lipolysis, thermogenesis, transcription",

author = "{Sveidahl Johansen}, Olivia and Tao Ma and Hansen, {Jakob Bondo} and Markussen, {Lasse Kruse} and Renate Schreiber and Laia Reverte-Salisa and Hua Dong and Christensen, {Dan Ploug} and Wenfei Sun and Thorsten Gnad and Iuliia Karavaeva and Nielsen, {Thomas Svava} and Sander Kooijman and Cheryl Cero and Oksana Dmytriyeva and Yachen Shen and Maria Razzoli and O'Brien, {Shannon L.} and Kuipers, {Eline N.} and Nielsen, {Carsten Haagen} and William Orchard and Nienke Willemsen and Jespersen, {Naja Zenius} and Morten Lundh and Sustarsic, {Elahu Gosney} and Hallgren, {Cecilie M{\o}rch} and Mikkel Frost and Seth McGonigle and Isidor, {Marie Sophie} and Christa Broholm and Oluf Pedersen and Hansen, {Jacob Bo} and Niels Grarup and Torben Hansen and Andreas Kj{\ae}r and Granneman, {James G.} and Babu, {M. Madan} and Davide Calebiro and S{\o}ren Nielsen and Mikael Ryd{\'e}n and Raymond Soccio and Rensen, {Patrick C.N.} and Treebak, {Jonas Thue} and Schwartz, {Thue Walter} and Brice Emanuelli and Alessandro Bartolomucci and Alexander Pfeifer and Rudolf Zechner and Camilla Scheele and Susanne Mandrup and Zachary Gerhart-Hines",

note = "Funding Information: We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the ?-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. This work was supported by the NIH, National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496, DK117504, and R56DK118150 to A.B.), the Austrian Science Fund (FWF) (F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project ?Generating the best evidence-based pharmaceutical targets for atherosclerosis? (CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling (ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G. 335447717/SFB1328 and 290847636/FOR2372 to A.P. and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406, grant ID PD007-18). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (https://cbmr.ku.dk/). D.C. is supported by a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z). Conceptualization, Z.G.-H. O.S.J. T.M. and Jakob Bondo Hansen; investigation, Z.G.-H. O.S.J. T.M. Jakob Bondo Hansen, L.K.M. R. Schreiber, L.R.-S. H.D. D.P.C. W.S. T.G. I.K. T.S.N. S.K. C.C. O.D. Y.S. M.R. S.L.O. E.N.K. C.H.N. W.O. N.W. N.Z.J. M.L. E.G.S. C.M.H. M.F. S. McGonigle, M.S.I. C.B. O.P. Jacob Bo Hansen, N.G. T.H. A.K. J.G.G. M.M.B. D.C. S.N. M.R. R. Soccio, P.C.N.R. J.T.T. T.W.S. B.E. A.B. A.P. R.Z. C.S. and S. Mandrup; writing ? original draft, Z.G.-H. and O.S.J.; writing ? review & editing, Z.G.-H. O.S.J. and T.M.; visualization, O.S.J. O.S.J. Jakob Bondo Hansen, D.P.C. T.W.S. and Z.G.-H. work or have worked, in some capacity, for Embark Biotech ApS, a company developing therapeutics for the treatment of diabetes and obesity. All other authors declare no competing interests associated with this manuscript. Funding Information: We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the β-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . This work was supported by the NIH , National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496 , DK117504 , and R56DK118150 to A.B.), the Austrian Science Fund (FWF) ( F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” ( CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling ( ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G., 335447717/SFB1328 and 290847636/FOR2372 to A.P., and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406 , grant ID PD007-18 ). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org ). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045 ). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation ( DNRF55 ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( https://cbmr.ku.dk/ ). D.C. is supported by a Wellcome Trust Senior Research Fellowship ( 212313/Z/18/Z ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = jun,

day = "24",

doi = "10.1016/j.cell.2021.04.037",

language = "English (US)",

volume = "184",

pages = "3502--3518.e33",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "13",

}

TY - JOUR

T1 - Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

AU - Sveidahl Johansen, Olivia

AU - Ma, Tao

AU - Hansen, Jakob Bondo

AU - Markussen, Lasse Kruse

AU - Schreiber, Renate

AU - Reverte-Salisa, Laia

AU - Dong, Hua

AU - Christensen, Dan Ploug

AU - Sun, Wenfei

AU - Gnad, Thorsten

AU - Karavaeva, Iuliia

AU - Nielsen, Thomas Svava

AU - Kooijman, Sander

AU - Cero, Cheryl

AU - Dmytriyeva, Oksana

AU - Shen, Yachen

AU - Razzoli, Maria

AU - O'Brien, Shannon L.

AU - Kuipers, Eline N.

AU - Nielsen, Carsten Haagen

AU - Orchard, William

AU - Willemsen, Nienke

AU - Jespersen, Naja Zenius

AU - Lundh, Morten

AU - Sustarsic, Elahu Gosney

AU - Hallgren, Cecilie Mørch

AU - Frost, Mikkel

AU - McGonigle, Seth

AU - Isidor, Marie Sophie

AU - Broholm, Christa

AU - Pedersen, Oluf

AU - Hansen, Jacob Bo

AU - Grarup, Niels

AU - Hansen, Torben

AU - Kjær, Andreas

AU - Granneman, James G.

AU - Babu, M. Madan

AU - Calebiro, Davide

AU - Nielsen, Søren

AU - Rydén, Mikael

AU - Soccio, Raymond

AU - Rensen, Patrick C.N.

AU - Treebak, Jonas Thue

AU - Schwartz, Thue Walter

AU - Emanuelli, Brice

AU - Bartolomucci, Alessandro

AU - Pfeifer, Alexander

AU - Zechner, Rudolf

AU - Scheele, Camilla

AU - Mandrup, Susanne

AU - Gerhart-Hines, Zachary

N1 - Funding Information: We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the ?-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. This work was supported by the NIH, National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496, DK117504, and R56DK118150 to A.B.), the Austrian Science Fund (FWF) (F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project ?Generating the best evidence-based pharmaceutical targets for atherosclerosis? (CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling (ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G. 335447717/SFB1328 and 290847636/FOR2372 to A.P. and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406, grant ID PD007-18). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation (DNRF55). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (https://cbmr.ku.dk/). D.C. is supported by a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z). Conceptualization, Z.G.-H. O.S.J. T.M. and Jakob Bondo Hansen; investigation, Z.G.-H. O.S.J. T.M. Jakob Bondo Hansen, L.K.M. R. Schreiber, L.R.-S. H.D. D.P.C. W.S. T.G. I.K. T.S.N. S.K. C.C. O.D. Y.S. M.R. S.L.O. E.N.K. C.H.N. W.O. N.W. N.Z.J. M.L. E.G.S. C.M.H. M.F. S. McGonigle, M.S.I. C.B. O.P. Jacob Bo Hansen, N.G. T.H. A.K. J.G.G. M.M.B. D.C. S.N. M.R. R. Soccio, P.C.N.R. J.T.T. T.W.S. B.E. A.B. A.P. R.Z. C.S. and S. Mandrup; writing ? original draft, Z.G.-H. and O.S.J.; writing ? review & editing, Z.G.-H. O.S.J. and T.M.; visualization, O.S.J. O.S.J. Jakob Bondo Hansen, D.P.C. T.W.S. and Z.G.-H. work or have worked, in some capacity, for Embark Biotech ApS, a company developing therapeutics for the treatment of diabetes and obesity. All other authors declare no competing interests associated with this manuscript. Funding Information: We thank the members of the Gerhart-Hines lab for discussions. We thank Katharina Stohlmann and Kirsten Langberg Meeske for technical assistance. The authors thank B.B. Lowell (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA) for providing the β-less mice. The Genotype-Tissue Expression (GTEx) Project used in this manuscript was supported by the Common Fund of the Office of the Director of the NIH and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . This work was supported by the NIH , National Institute of Digestive Diabetes and Kidney Diseases (grants DK102496 , DK117504 , and R56DK118150 to A.B.), the Austrian Science Fund (FWF) ( F73 SFB LIPID HYDROLYSIS to R. Schreiber and R.Z.), the Cardiovascular Research Netherlands for the GENIUS-2 project “Generating the best evidence-based pharmaceutical targets for atherosclerosis” ( CVON 2017-20 to P.C.N.R.), the Novo Nordisk Scholarship Programme (to O.S.J.), the Novo Nordisk Foundation (project grant NNF18OC0034364 to Z.G.-H.), the Center for Adipocyte Signaling ( ADIPOSIGN to S. Mandrup and NNF15CC0018486 and NNF15SA0018346 to M.R.), the Independent Research Fund Denmark (Sapere Aude starting grant 4002-00024 to Z.G.-H. and DFF-7016-00279 to S. Mandrup), the Diabetes Research Program at Karolinska Institutet (to M.R.), the Swedish Research Council (to M.R.), CIMED (to M.R.), the Swedish Diabetes Foundation (to M.R.), the Knut and Alice Wallenberg Foundation (to M.R.), the Stockholm County Council (to M.R.), and the Deutsche Forschungsgemeinschaft (German Research Foundation project number 289107305 to T.G., 335447717/SFB1328 and 290847636/FOR2372 to A.P., and 214362475/GRK1873/2 to L.R.-S.). N.Z.J. is supported by an independent fellowship from Danish Diabetes Academy (DDA) supported by the Novo Nordisk Foundation (grant number NNF17SA0031406 , grant ID PD007-18 ). The genetic analysis was supported by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care (LuCAMP, http://www.lucamp.org ). This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement no. 639382 to Z.G.-H.). The Centre for Physical Activity Research (CFAS) is supported by TrygFonden (grants ID 101390 and ID 20045 ). During the study period, the Centre of Inflammation and Metabolism (CIM) was supported by a grant from the Danish National Research Foundation ( DNRF55 ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation ( https://cbmr.ku.dk/ ). D.C. is supported by a Wellcome Trust Senior Research Fellowship ( 212313/Z/18/Z ). Publisher Copyright: © 2021 The Author(s)

PY - 2021/6/24

Y1 - 2021/6/24

N2 - Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

AB - Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

KW - adrenergic receptor

KW - brown adipose tissue

KW - constitutively active

KW - energy expenditure

KW - G protein-coupled receptor

KW - GPCR

KW - GPR3

KW - lipolysis

KW - thermogenesis

KW - transcription

UR - http://www.scopus.com/inward/record.url?scp=85107638718&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85107638718&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.04.037

DO - 10.1016/j.cell.2021.04.037

M3 - Article

C2 - 34048700

AN - SCOPUS:85107638718

SN - 0092-8674

VL - 184

SP - 3502-3518.e33

JO - Cell

JF - Cell

IS - 13

ER -

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis

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