小柯机器人

丹麦哥本哈根大学Zachary Gerhart-Hines研究团队发现，脂解驱动组成型活化受体GPR3的表达，从而诱导脂肪细胞产热。相关论文于2021年5月27日在线发表于国际学术期刊《细胞》。

研究人员通过组成型活化受体GPR3揭示G蛋白偶联受体（GPCR）介导的脂肪生成的一种替代性范式。结果表明，GPR3的N末端赋予本质性的信号传导活性，导致连续的GS耦合和营养生产，而不需要外源配体。因此，GPR3的转录诱导表明与常规GPCR配体结合的调节能力平行存在。因此，在产热脂肪细胞中增加GPR3表达足以促进小鼠的能量消耗和代谢疾病抵抗。GPR3转录通过脂肪溶解信号来实现冷激活，并且膳食脂肪增强GPR3依赖性热生成，从而扩增对热量过量的反应。此外，研究人员发现GPR3是人类棕色脂肪细胞的必需肾上腺素非依赖性调控因子。

这些研究结果揭示了一种通过脂解诱导组成型活化型GPR3表达的GPCR调控和产热激活的非经典机制。

据介绍，热生脂肪细胞具有能量消耗的能力，其通过β-肾上腺素能GPCR的配体依赖性活化所诱导。

附：英文原文

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

Author: 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 Mrch Hallgren, Mikkel Frost, Seth McGonigle, Marie Sophie Isidor, Christa Broholm, Oluf Pedersen, Jacob Bo Hansen, Niels Grarup, Torben Hansen, Andreas Kjr, James G. Granneman, M. Madan Babu, Davide Calebiro, Sren 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

Issue&Volume: 2021-05-27

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.

DOI: 10.1016/j.cell.2021.04.037

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00572-9