Here we demonstrate that guar gum supplementation works in the same way as SCFAs in the protection against HFD-induced obesity and insulin resistance, namely by repressing PPARγ expression, subsequently increasing mitochondrial UCP2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced fatty-acid oxidation in both liver and adipose tissue. This evidence concerns the gene UCP2 and obesity due to melanocortin 4 receptor deficiency.