FGF21 mediates the “paradoxical” resistance to diet-induced obesity in UCP1-deficient mice

Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is extensively investigated to correct diet-induced obesity (DIO) and comorbidities. UCP1-deficient (KO) mice at thermoneutrality are slightly obesity prone indeed, but their 'paradoxical resistance to DIO' at room temperature has remained an unexplained phenomenon. Here we show that molecular networks controlled by increased endogenous FGF21 are solely responsible for DIO-resistance using UCP1-FGF21 double knockout mice. Global transcriptomic analysis identifies FGF21-controlled lipid and oxidative metabolism specifically in beige adipose tissue. However, comprehensive mouse metabolic phenotyping reveals no differences in energy expenditure, food intake and assimilation, the latter supported by similar gut microbial diversity and metabolism. Instead, increased drinking of UCP1 KO is accompanied by increased excretion of amino acids and carnitine-based metabolites. Our study solves the control of “paradoxical” DIO resistance in the absence of UCP1 and highlights new underappreciated routes of energy loss via urine that call for future attention in field of metabolic diseases.