Increased whole body energy expenditure and protection against diet-induced obesity in Cyp8b1-deficient mice is accompanied by altered adipose tissue features.

The aim of this study was to elucidate mechanisms whereby bile acids exert beneficial metabolic effects, using the mouse as model. These mice are unable to synthesize cholic acid, resulting in increased synthesis of chenodeoxycholic acid and enlarged bile acid pool. mice were found to be protected against high-fat diet induced obesity. Bomb calorimetry measurements showed increased faecal energy output in mice. Indirect calorimetry measurements demonstrated increased energy expenditure in mice. Meal tolerance tests revealed no differences in glucose disposal, but the insulin response was lower in mice. Intravenous glucose tolerance tests, as well as static incubations of isolated islets, showed no difference between the groups, whereas insulin tolerance tests demonstrated improved insulin sensitivity in mice. The genes encoding mitochondrial transcription factor A (TFAM) and type 2-iodothyronine deiodinase were upregulated in brown adipose tissue of mice and Western blot analyses showed increased abundance of TFAM, and a trend towards increased abundance of UCP1. The upregulation of TFAM and UCP1 was accompanied by increased mitochondrial density, as shown by transmission electron microscopy. White adipocytes of mice exhibited increased responsiveness to both catecholamines and insulin in lipolysis experiments and increased insulin-stimulated lipogenesis. In conclusion, increased energy expenditure, mitochondrial density of brown adipocytes and faecal energy output may all contribute to the protection against diet-induced obesity of mice. Enhanced insulin sensitivity of mice is accompanied by increased hormonal responsiveness of white adipocytes.