B6 - The Functional Relevance of Adhesion GPCR in Adipose Tissue
Genome-wide association studies and transcriptomic data related several adhesion G protein-coupled receptors (aGPCRs) to metabolic characteristics such as obesity (GPR133/ADGRD1) or LDL cholesterol levels (CELSR2/ADGRC2). This family of receptors is defined by their large size and modular composition. Only recent discoveries have provided an understanding of the mechanisms that govern the activation of these GPCRs. It is thought that aGPCR incitement requires the interplay between endogenous ligands, the tethered agonist sequence and mechanical force. This rather unusual mode of action might unravel unknown principles of metabolic regulation and adipocyte function and may lead to the discovery of new treatment paradigms.
Little is known about the role of aGPCRs in adipose tissue. In example, one representative, GPR116/ADGRF5, has been shown to be critical for adipocyte differentiation in vitro. The same study reported glucose intolerance and insulin resistance in mice when specifically knocked out in adipose tissue. The scarce published data available claims only one other aGPCR, namely CD97/ADGRE5, to be expressed in adipocytes. Yet, our own preliminary data suggest a regulated expression of at least two other aGPCRs, GPR133 and Celsr2, during adipocyte differentiation. In this project, we clarify the functional relevance of aGPCRs in adipose tissue. Thus, the expression profiles of all aGPCRs in white and brown adipose tissue at several differentiation states will be determined. Further, we will determine the effect of aGPCR activation on adipocyte function regarding lipolysis, glucose uptake, cell respiration, and hormone expression and secretion in adipocytes.
Figure 1: Adhesion G protein-coupled receptors (aGPCRs) modulate adipocyte function. Several members of the aGPCR family have been identified to be differentially regulated in adipocytes and adipose tissue. We propose that aGPCRs can modify adipocyte function and fatty acid composition through G protein-mediated functions in vitro and in vivo.
PKA: protein kinase A, HSL: hormone-sensitive lipase, ATGL: adipose triglyceride lipase, TG: triglyceride, FFA: free fatty acid, p116: agonistic peptide of GPR116 (an aGPCR that is endogenously expressed in adipose tissue), w/o: without.
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