To put the puzzle together, the evidence suggests that (i) the combination of LFD and TM improves body weight, circulating FGF21 concentration and behavioural parameters; (ii) the dietary switch to LFD and LFD with TM are very likely to interrupt the vicious circle of obesity; and (iii) FGF21 can be considered as a potential biomarker for improved behaviour after weight reduction, since an improvement in behaviour is associated with a lower FGF21 concentration. This evidence concerns the gene FGF21 and obesity due to melanocortin 4 receptor deficiency.