Thus, as evident from our early preclinical studies (Gault et al. 2005, McClean et al. 2007), diminished action or antagonism of GIP substantially decreases obesity-driven insulin resistance by depleting liver triglycerides, reducing adiposity, and thereby substantially diminishing insulin demand with the induction of beneficial beta-cell rest and decreased circulating insulin. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.