Experimentally it was identified that systemic knockout mice for βK (Klb−/−) were protected against HF DIO.401 The lack of βK was found to shift BA pool composition to favor the classical pathway to produce a higher fraction of DCA, a highly potent TGR5 agonist.402 Reduced TGR5 agonism would result in reduced basal metabolic rate and reduced incretin release, predisposing for obesity. This evidence concerns the gene GPBAR1 and obesity due to melanocortin 4 receptor deficiency.