Mice Lacking Gpr75 are Hypophagic and Thin

Abstract

Purpose: Humans with haploinsufficiency of GPR75, an orphan GPCR, are thin. Gpr75 knockout (KO) mice are also thin with improved glucose homeostasis. We wanted to confirm these findings in Gpr75 KO mice and determine whether decreased energy intake and/or increased energy expenditure contributed to the thin phenotype. Methods: Gpr75 KO mice were generated by homologous recombination. All studies compared female and male Gpr75 KO mice to their wild type (WT) littermates. Body composition was measured by DXA and QMR technologies. Glucose homeostasis was evaluated by measuring glucose and insulin levels during oral glucose tolerance tests (OGTTs). Food intake was measured in group-housed mice. In singly housed mice, energy expenditure was measured in Oxymax indirect calorimetry chambers, and locomotor activity was measured in Oxymax and Photobeam Activity System chambers. Results: In all 12 cohorts of adult female or male mice, Gpr75 KO mice had less body fat; pooled data showed that, compared to WT littermates (n = 103), Gpr75 KO mice (n = 118) had 49% less body fat and 4% less LBM (P < 0.001 for each). KO mice also had 8% less body fat at weaning (P < 0.05), and during the month after weaning as the thin phenotype became more exaggerated, Gpr75 KO mice ate significantly less than, but had energy expenditure and activity levels comparable to, their WT littermates. During OGTTs, Gpr75 KO mice showed improved glucose tolerance (glucose AUC 23% lower in females, P < 0.05, and 26% lower in males, P < 0.001), accompanied by significantly decreased insulin levels and significantly increased insulin sensitivity indices. Conclusion: Gpr75 KO mice are thin at weaning, are hypophagic as the thin phenotype becomes more exaggerated, and exhibit improved glucose tolerance and insulin sensitivity as healthy-appearing adults. These results suggest that inhibiting GPR75 in obese humans may safely decrease energy intake and body fat while improving glucose tolerance and insulin sensitivity.

Mice deficient for G‐protein‐coupled receptor 75 display altered presynaptic structural protein expression and disrupted fear conditioning recall

“…In an effort to compare the basic characteristics of this model with the existing human and pre-clinical data, we assessed the body weight of two separate cohorts of mice at 12 and 26 weeks of age given free access to standard (i.e., non-high-fat) rodent chow. We found that 26-week-old GPR75KO males (n = 26), but not females (n = 25) mice, were resistant to age-related gains in body mass (Figure S1), confirming previous studies that the perturbations in GPR75 expression are associated with reduction in body fat in mice and a lower prevalence of obesity in humans (Akbari et al, 2021;Powell et al, 2022).…”

“…GPR75 is no exception to these issues. Recent reports describe the activation of GPR75 by 20‐HETE, which seems to play a role in the general metabolism that promotes obesity (Akbari et al, 2021; Gilani et al, 2021; Liu et al, 2013; Powell et al, 2022). Less is known about the function of GPR75 in the mature brain.…”

“…We first assessed anxiety-like behaviors in the elevated plus maze between the genotypes in this study. Within a single 10-minute exposure to the appa- Powell et al, 2022). Less is known about the function of GPR75 in the mature brain.…”

“…Several existing reports indicate that GPR75 mRNA is expressed in the periphery (Liu et al, 2013) as well as in several brain areas (Sjostedt et al, 2020). In the periphery, this receptor appears to play a role in hypertension (Garcia et al, 2017), obesity (Akbari et al, 2021), glucose homeostasis (Liu et al, 2013; Powell et al, 2022), and prostate cancer (Cardenas et al, 2020). Less is known about the cellular localization and function of GPR75 in the brain.…”

Cryo-EM complex structure of active GPR75 with a nanobody

“…GPR75 is a member of the G protein-coupled receptor family and is a novel target for the clinical treatment of obesity 7 . Human GPR75 haploinsufficiency exhibits a striking phenotype of low body fat, and GPR75 knockout mice are hypophagic and thin, improving glucose tolerance and insulin sensitivity 8 . GPR75 was first cloned and identified as an orphan GPCR in the human retinal pigment epithelium and different brain region 9 .…”