Glucagon secretion from islets isolated from HFHS-diet-fed mice of both genotypes was ~1.7-fold higher relative to islets from chow-fed mice (Fig. 1h, i) (islet glucagon secretion pg/islet/h at 1mmol/l glucose: chow-fed control 11.48 ± 1.50 vs. HFHS-fed control 19.58 ± 1.55, P = 0.0045; chow-fed gluACC1KO 6.76 ± 1.05 vs. HFHS-fed gluACC1KO 11.31 ± 1.72, P = 0.0123; mean ± SEM, t-test), demonstrating that gluACC1KO mice have the same ability as control mice to increase overall glucagon secretion in response to a chronic dietary challenge and associated obesity. Here, GCG is linked to obesity due to melanocortin 4 receptor deficiency.