Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.
Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.
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脂解驱动组成型活性受体GPR3的表达以诱导脂肪产热。
DOI：
10.1016/j.cell.2021.04.037
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发表时间：
2021-06-24
期刊：
影响因子：
64.5
通讯作者：
Gerhart-Hines Z
中科院分区：
文献类型：
--
作者：
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
产热性脂肪细胞具有治疗上吸引人的能量消耗能力，这是通过β-肾上腺素能G蛋白偶联受体（GPCR）的配体依赖性激活来典型地冷诱导的。在这里，我们发现了一个替代范例的GPCR介导的脂肪产热通过组成型活性受体，GPR 3。我们发现，GPR 3的N末端赋予内在的信号传导活性，导致连续的GS-耦合和cAMP的生产，而无需外源性配体。因此，Gpr 3的转录诱导代表与常规GPCR的配体结合平行的调节。因此，仅增加产热脂肪细胞中的Gpr 3表达就足以驱动小鼠的能量消耗并对抗代谢疾病。GPR 3转录是由脂解信号冷刺激的，并且膳食脂肪增强GPR 3依赖性产热以放大对热量过量的响应。此外，我们发现GPR 3是一个必不可少的，肾上腺素非依赖性调节人棕色脂肪细胞。总之，我们的研究结果揭示了一个非经典的机制，GPCR控制和产热激活通过脂解诱导的表达组成型活性GPR 3。GPR 3是棕色和米色脂肪组织中的冷诱导的GS偶联受体。在冷暴露期间，非典型脂解信号触发GPR 3转录。GPR 3是小鼠和人产热脂肪细胞的非肾上腺素能激活剂。诱导的脂解驱动组成型活性GPCR的表达，该GPCR调节小鼠和人脂肪细胞中的产热，而不依赖于交感神经或肾上腺素能输入
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. Gpr3 is a cold-induced Gs-coupled receptor in brown and beige adipose tissue A noncanonical lipolytic signal triggers Gpr3 transcription during cold exposure GPR3 is a nonadrenergic activator of mouse and human thermogenic adipocytes GPR3 drives thermogenesis without a ligand via its intrinsic Gs-coupling activity Cold-induced lipolysis drives the expression of a constitutively active GPCR that regulates thermogenesis in mouse and human adipocytes independent of sympathetic or adrenergic inputs.
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影响因子：
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作者：
Arner E;Mejhert N;Kulyté A;Balwierz PJ;Pachkov M;Cormont M;Lorente-Cebrián S;Ehrlund A;Laurencikiene J;Hedén P;Dahlman-Wright K;Tanti JF;Hayashizaki Y;Rydén M;Dahlman I;van Nimwegen E;Daub CO;Arner P
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