Human GPR75 Stable Cell Line - HEK293

Obesity imposes a heavy and escalating global disease burden. Body fat content is highly heritable, and human genetic studies help elucidate underlying biological mechanisms and suggest therapeutic avenues. Whole-exome sequencing of hundreds of thousands of individuals powerfully complements previous obesity genetics research, offering the potential to identify rare protein-coding variants with significant phenotypic impact. Here, researchers identified 16 genes where the burden of rare non-synonymous variants showed a statistically significant association with body mass index (BMI) at the whole-exome level; these included five genes encoding G protein-coupled receptors expressed in the brain (CALCR, MC4R, GIPR, GPR151, and GPR75). Genes highly expressed in the hypothalamus-a critical hub for the neuroendocrine regulation of energy balance-were significantly enriched among these associated genes. The study found that approximately 4 in 10,000 individuals carried protein-truncating variants in the GPR75 gene; heterozygous carriers exhibited a BMI reduction of 1.8 kg/m², a weight loss of 5.3 kg, and a 54% lower risk of obesity. In mouse models, Gpr75 knockout conferred resistance to weight gain under a high-fat diet; this effect was allele-dose dependent and accompanied by improved glycemic control and insulin sensitivity. These results suggest that inhibiting GPR75 could be a strategy for treating obesity, while also highlighting the immense potential of large-scale exome sequencing to identify high-impact coding variants and drug targets associated with complex traits.

Researchers expressed the two most frequent BMI-associated pLOF variants (minor allele count ≥ 10) in vitro; the results showed that they caused the truncated receptors to be retained intracellularly, likely resulting in a complete loss of receptor function (Figure 3). All experiments were conducted in HEK293 cells transfected with a GFP control plasmid (Control), wild-type GPR75 (GPR75), GPR75-Ala110fs, or GPR75-Gln234* plasmids. The researchers hypothesized that the loss of functional copies (i.e., haploinsufficiency) or the production of truncated proteins that interfere with receptor multimerization (i.e., a dominant-negative effect) might explain the association between GPR75 truncation variants and lower BMI.

Figure 1. In vitro expression studies of two predicted loss-of-function genetic variants in GPR75. (Akbari P, et al., 2021)