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

Metabolism and Systems Research

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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
Pages (from-to)	3502-3518.e33
Number of pages	51
Journal	Cell
Volume	184
Issue number	13
DOIs	https://doi.org/10.1016/j.cell.2021.04.037
Publication status	Published - 24 Jun 2021

Bibliographical note

Keywords

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

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

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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

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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 = "G protein-coupled receptor, GPCR, GPR3, adrenergic receptor, brown adipose tissue, constitutively active, energy expenditure, 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{\textquoteright}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",

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language = "English",

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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

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

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 - G protein-coupled receptor

KW - GPCR

KW - GPR3

KW - adrenergic receptor

KW - brown adipose tissue

KW - constitutively active

KW - energy expenditure

KW - lipolysis

KW - thermogenesis

KW - transcription

UR - http://www.scopus.com/inward/record.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

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Cite this