GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1

Abstract

Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.

Structure of the GOLD-domain seven-transmembrane helix protein family member TMEM87A

“…While three newly identified GOST proteins have been minimally characterized to date (prior work has associated GPR180 with TGF-B signaling and TMEM181 with Escherichia coli CDT toxicity Balazova et al, 2021 ; Carette et al, 2009 ), WLS (also known as GPR177 or evenness interrupted homolog [EVI]) has been extensively studied. WLS plays an essential role in chaperoning lipidated and secreted Wnt signaling proteins between internal membranes and the cell surface ( Bänziger et al, 2006 ; Bartscherer et al, 2006 ; Fu et al, 2009 ).…”

“…Similarity to canonical GPCRs in the transmembrane region raises the question of whether TMEM87A or other GOST proteins are competent for GPCR signaling. While ligands have been proposed for some GOST proteins, specifically, neurostatin for GPR107 and L-lactate for GPR180, no definitive molecular evidence of G-protein signaling has been reported for any family member and GPR180 has been reported not to signal as a GPCR ( Balazova et al, 2021 ; Mosienko et al, 2018 ; Yosten et al, 2012 ). The position of helix 8 in TMEM87A is sterically incompatible with G-protein or arrestin binding and predicted structures of other GOST proteins present similar steric blocks.…”

Structure of the GOLD-domain seven-transmembrane helix protein family member TMEM87A

“…While three newly identified GOST proteins have been minimally characterized to date (prior work has associated GPR180 with TGF-B signaling and TMEM181 with E. coli cytolethal distending toxin toxicity 33,34 ), WLS (also known as GPR177 or evenness interrupted homolog (EVI)) has been extensively studied. WLS plays an essential role in chaperoning lipidated and secreted Wnt signaling proteins between internal membranes and the cell surface 35–37 .…”

“…Similarity to canonical GPCRs in the transmembrane region raises the question of whether TMEM87A or other GOST proteins are competent for GPCR signaling. While ligands have been proposed for some GOST proteins, specifically, neurostatin for GPR107 and L-lactate for GPR180, no definitive molecular evidence of G-protein signaling has been reported for any family member and GPR180 has been reported not to signal as a GPCR 33,40,41 . The position of helix 8 in TMEM87A is sterically incompatible with G-protein or arrestin binding and predicted structures of other GOST proteins present similar steric blocks.…”

Sodium butyrate attenuated diet-induced obesity, insulin resistance and inflammation partly by promoting fat thermogenesis via intro-adipose sympathetic innervation

“…This process is the so-called “WAT browning” ( Becher et al, 2021 ). Multiple studies have shown that increasing brown and beige fat activity can effectively increase whole-body energy expenditure, which can be used therapeutically to reduce diet-induced obesity and the associated complications ( Balazova et al, 2021 ; Cui et al, 2021 ).…”