Profiling of G-Protein Coupled Receptors in Adipose Tissue and Differentiating Adipocytes Offers a Translational Resource for Obesity/Metabolic Research

Abstract

G protein-coupled receptors (GPCRs) are expressed essentially on all cells, facilitating cellular responses to external stimuli, and are involved in nearly every biological process. Several members of this family play significant roles in the regulation of adipogenesis and adipose metabolism. However, the expression and functional significance of a vast number of GPCRs in adipose tissue are unknown. We used a high-throughput RT-PCR panel to determine the expression of the entire repertoire of non-sensory GPCRs in mouse white, and brown adipose tissue and assess changes in their expression during adipogenic differentiation of murine adipocyte cell line, 3T3-L1. In addition, the expression of GPCRs in subcutaneous adipose tissues from lean, obese, and diabetic human subjects and in adipocytes isolated from regular chow and high-fat fed mice were evaluated by re-analyzing RNA-sequencing data. We detected a total of 292 and 271 GPCRs in mouse white and brown adipose tissue, respectively. There is a significant overlap in the expression of GPCRs between the two adipose tissue depots, but several GPCRs are specifically expressed in one of the two tissue types. Adipogenic differentiation of 3T3-L1 cells had a profound impact on the expression of several GPCRs. RNA sequencing of subcutaneous adipose from healthy human subjects detected 255 GPCRs and obesity significantly changed the expression of several GPCRs in adipose tissue. High-fat diet had a significant impact on adipocyte GPCR expression that was similar to human obesity. Finally, we report several highly expressed GPCRs with no known role in adipose biology whose expression was significantly altered during adipogenic differentiation, and/or in the diseased human subjects. These GPCRs could play an important role in adipose metabolism and serve as a valuable translational resource for obesity and metabolic research.

Genome-wide association study (GWAS) identified PCOS susceptibility variants and replicates reported risk variants

“…RBM11 gene represented as member of RNA binding protein has functional impact in ovarian cancer development and invasion through the activation of Akt/mTOR signaling pathway [41]. Several G-protein coupled receptors (GPCRs) have been reported among adipose tissues, but GPR12 detected only in white adipose tissue in a vitro study and its signi cant expression in adipocytes to impact obesity RNA sequence and adipose metabolism observed [42]. Another study performed in model organism to understand its mechanism evidenced that de ciency of GPR12 responsible for development of high body mass index, obesity and low energy expenditure which is valuable for its therapeutic target in PCOS patients [43].…”

G protein-coupled receptor 146: new insights from genetics and model systems

“…GPR146 emerged as one of the most significantly downregulated genes in both groups of obese individuals. Further investigations revealed a significant increased expression of Gpr146 specifically on day 7 of 3T3-L1 differentiation from preadipocytes into adipocytes [17]. However, the precise role of GPR146 in adipose tissue remains unclear.…”

“…However, the adipocyte-specific deletion of Gpr146 in mice did not affect plasma cholesterol levels [4]. Mahri et al [17] conducted a comprehensive high-throughput RT-qPCR assay to profile nonsensory GPRs in subcutaneous adipose tissues (sAT) from lean, healthy-obese (without diabetes, BMI: 30–49.9 kg/m 2 ), and unhealthy obese (with diabetes, BMI: 30–49.9 kg/m 2 ) individuals. GPR146 emerged as one of the most significantly downregulated genes in both groups of obese individuals.…”

Metabolite-sensing GPCRs controlling interactions between adipose tissue and inflammation

“…A similar increase in HCA 2 expression in response to LPS is also observed in cultured adipocyte models in vitro ( 66 ). In contrast, adipocyte HCA 2 expression decreases in diet induced obese mice ( 66 ), and expression is decreased in subcutaneous adipose tissue of obese human subjects ( 67 ). These contrasting in vitro and in vivo findings may suggest that simple treatment of in vitro adipocytes with pro-inflammatory mediators does not accurately reproduce the chronic multicellular inflammatory responses observed in obese adipose ( 68 ).…”