Mice Lacking are Hypophagic and Thin.

Purpose: Humans with haploinsufficiency of , an orphan GPCR, are thin. knockout (KO) mice are also thin with improved glucose homeostasis. We wanted to confirm these findings in KO mice and determine whether decreased energy intake and/or increased energy expenditure contributed to the thin phenotype.

Methods: KO mice were generated by homologous recombination. All studies compared female and male 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, KO mice had less body fat; pooled data showed that, compared to WT littermates (n = 103), KO mice (n = 118) had 49% less body fat and 4% less LBM ( < 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, KO mice ate significantly less than, but had energy expenditure and activity levels comparable to, their WT littermates. During OGTTs, KO mice showed improved glucose tolerance (glucose AUC 23% lower in females, < 0.05, and 26% lower in males, P < 0.001), accompanied by significantly decreased insulin levels and significantly increased insulin sensitivity indices.

Conclusion: 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.