In summary, we demonstrated that pomelo peel extracts had several beneficial effects on HF diet-fed mice, possibly though the activation of PPARα and GLUT4, resulting in prevention of the development of obesity induced by a HF diet, attenuation of dyslipidemia and hyperglycemia, improved glucose tolerance and insulin resistance. Here, SLC2A4 is linked to obesity due to melanocortin 4 receptor deficiency.