A recent well-controlled crossover isocaloric feeding study in adults with overweight/obesity reported a decline in insulin sensitivity, reduction in glucose disposal rate by − 0.37 ± 0.15 mmol/min measured by hyperinsulinemic-euglycemic clamp, after 4 weeks of high-fat/high-saturated fat diet compared to a low-fat diet (glucose disposal rate + 0.12 ± 0.11 mmol/min, P < 0.01) [41]. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.