Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis
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Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis. / Sveidahl Johansen, Olivia; Ma, Tao; Hansen, Jakob Bondo; Markussen, Lasse Kruse; Schreiber, Renate; Reverte-Salisa, Laia; Dong, Hua; Christensen, Dan Ploug; Sun, Wenfei; Gnad, Thorsten; Karavaeva, Iuliia; Nielsen, Thomas Svava; Kooijman, Sander; Cero, Cheryl; Dmytriyeva, Oksana; Shen, Yachen; Razzoli, Maria; O'Brien, Shannon L; Kuipers, Eline N; Nielsen, Carsten Haagen; Orchard, William; Willemsen, Nienke; Jespersen, Naja Zenius; Lundh, Morten; Sustarsic, Elahu Gosney; Hallgren, Cecilie Mørch; Frost, Mikkel; McGonigle, Seth; Isidor, Marie Sophie; Broholm, Christa; Pedersen, Oluf; Hansen, Jacob Bo; Grarup, Niels; Hansen, Torben; Kjær, Andreas; Granneman, James G; Babu, M Madan; Calebiro, Davide; Nielsen, Søren; Rydén, Mikael; Soccio, Raymond; Rensen, Patrick C N; Treebak, Jonas Thue; Schwartz, Thue Walter; Emanuelli, Brice; Bartolomucci, Alessandro; Pfeifer, Alexander; Zechner, Rudolf; Scheele, Camilla; Mandrup, Susanne; Gerhart-Hines, Zachary.
In: Cell, Vol. 184, No. 13, 2021, p. 3502-3518 +.Research output: Contribution to journal › Journal article › Research › peer-review
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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 - Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2021
Y1 - 2021
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.
U2 - 10.1016/j.cell.2021.04.037
DO - 10.1016/j.cell.2021.04.037
M3 - Journal article
C2 - 34048700
VL - 184
SP - 3502-3518 +
JO - Cell
JF - Cell
SN - 0092-8674
IS - 13
ER -
ID: 271986976