Some individuals are more prone to weight gain whilst others remain resistant following consumption of a high-energy diet (HED). The exact mechanism(s) underpinning this difference are not fully understood. We have generated a model of diet-induced obesity in female isogenic C57Bl6/J mice in which those that gained 25% more weight following 6 weeks of a HED were classified as DIO and those that had similar weight gain to the chow-fed C57Bl6/J mice classified as resistant (DR). Reduced energy intake (by 30% calories), but not energy expenditure (resting, voluntary or spontaneous), contributed to diet-induced obesity resistance. Further examination of the classical central appetite regulatory genes (NPY, AgRP, POMC) were found not to be the predominant drivers of this difference implicating a greater contribution from peripheral mechanisms. Therefore the aim was to identify what peripheral pathways are involved to promote diet-induced obesity resistance in our mice. The gut has now been touted as a ‘second brain’ and highly important in the regulation of appetite and body weight. We therefore measured gene expression levels of several key ileal specific G-coupled protein receptors (GPRs) involved in fatty acid sensing. GPR40 was significantly reduced in the DR mice (by 55%) whilst GPR120, GPR119 and GPR41 were all significantly increased compared to DIO mice (47%, 40%, 35% respectively, p<0.05). GPR43 gene expression trended upwards (p<0.07). Interestingly, GPR41 and GPR43 are known to co-localise with GLP-1, a potent appetite suppressor which we found to be significantly increased in the DR mice (by 57%, p<0.05). Together, our data suggest that gut specific GPR expression changes, particularly GPR41 and GPR43, modulate downstream expression of GLP-1, in turn leading to reduced energy intake and weight gain resistance in our DR mice. Therefore, the gut and their nutrient responsive receptors are important players in conferring resistance to diet-induced obesity in mice.