A rare human variant that disrupts GPR10 signalling causes weight gain in mice

Abstract

Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impair ligand binding and G protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an individual with obesity, gain excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy.

Fig. 1. Functional characterisation of rare variants in GPR10 identified in cases with severe obesity and controls.

a Rare variants identified in individuals with severe early onset obesity (magenta) and in controls (blue) shown on a schematic of the GPR10 protein and b on a structural model. For residues located in α-helices, a generic residue number according to a structure-based GPCRdb numbering scheme shown in subscript. Wild-type (WT) and mutant forms of GPR10 were studied in cells alongside a low frequency variant (P305L); mock transfected cells served as a negative control. Effects on ligand (PrRP-31)-induced binding c and d receptor-mediated activation of Gα_q/11-regulated inositol triphosphate signalling in transiently transfected COS-7 cells. Data shown as sum curves from 3-9 experiments normalized to WT maximal binding/response±SEM. e COS-7 cells were transiently co-transfected with WT and varying amounts of mutant GPR10 to investigate dominant negative effects on PrRP-31-induced Gα_q/11-regulated inositol triphosphate signalling. Mean±SEM of 4 experiments are shown; differences between means for 2.5 ng WT alone and with additional 2.5 ng mutant GPR10 were compared with Students t-test, ns – not significant; ^**p < 0.01; ^***p < 0.001 (based on data shown in Supplementary Fig. 1, panels d-i). Source data are provided as a Source Data file.

Fig. 2. Obesity in Gpr10^-/- knockout mice.

a, b Body weight curves for male and female homozygous wild-type Gpr10^+/+ (grey squares) and Gpr10^-/- null mice (red circles) (males, n = 21-25 per group; females, n = 6 per group). Data are presented as mean±SEM and analysed with a mixed-effects analysis followed by Sidak’s multiple-comparison post hoc test. c Daily food intake (g) in 6 week old homozygous wild-type Gpr10^+/+ (grey squares; n = 5) and Gpr10^-/- null mice (red circles; n = 6) fed on normal chow. Data are presented as mean±SEM and comparisons made using two-tailed Student’s t-test. d, e Oxygen consumption (VO₂, ml/h) for male wild-type Gpr10^+/+ (grey squares) and Gpr10^-/- null mice (red circles) at 6 weeks across the light-dark cycle (n = 5 in each group). Data are presented as mean±SEM and comparisons made using two-way ANOVA followed by Bonferroni’s multiple-comparison post hoc tests. Source data are provided as a Source data file.

Fig. 3. Obesity in Gpr10^P193S/P193S mutant mice.

a, b Body weight curves of wild-type (^+/+; grey squares), heterozygous (^+/P193S; purple triangles) and homozygous Gpr10^P193S/P193S (pink circles) male (n = 9, 18 and 7 respectively) and female mice (n = 8, 8 and 5 respectively) maintained on 60% high energy diet from 8 weeks. Data are presented as mean± SEM and were analysed with a mixed-effects analysis followed by Sidak’s multiple-comparison post hoc test. c Daily food intake (g) in wild-type (^+/+; grey squares), heterozygous (^+/P193S; purple triangles) and homozygous Gpr10^P193S/P193S (pink circles) male mice aged 8 weeks on normal chow (n = 12, 13 and 13 respectively). d, e Oxygen consumption (VO₂, ml/hr) across the light-dark cycle in male wild-type (^+/+; grey squares), heterozygous (^+/P193S; purple triangles) and homozygous Gpr10^P193S/P193S (pink circles) mice on standard chow at 8 weeks (n = 9, 9 and 11 respectively). Data are presented as mean ± SEM and comparisons made using two-way ANOVA followed by Bonferroni’s multiple-comparison post hoc tests. Source data are provided as a Source data file.