OBJECTIVEBile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.RESEARCH DESIGN AND METHODSHere, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.RESULTSFXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.CONCLUSIONSOverall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.

Nutrition research is struggling to demonstrate beneficial health effects, since nutritional effects are often subtle and long term. Health has been redefined as the ability of our body to cope with daily-life challenges. Physiology acts as a well-orchestrated machinery to adapt to the continuously changing environment. We term this adaptive capacity “phenotypic flexibility.” The phenotypic flexibility concept implies that health can be measured by the ability to adapt to conditions of temporary stress, such as physical exercise, infections or mental stress, in a healthy manner. This may offer a more sensitive way to assess changes in health status of healthy subjects. Here, we performed a systematic review of 61 studies applying different nutritional stress tests to quantify health and nutritional health effects, with the objective to define an optimal nutritional stress test that has the potential to be adopted as the golden standard in nutrition research. To acknowledge the multi-target role of nutrition, a relevant subset of 50 processes that govern optimal health, with high relevance to diet, was used to define phenotypic flexibility. Subsequently, we assessed the response of biomarkers related to this subset of processes to the different challenge tests. Based on the obtained insights, we propose a nutritional stress test composed of a high-fat, high-caloric drink, containing 60 g palm olein, 75 g glucose and 20 g dairy protein in a total volume of 400 ml. The use of such a standardized nutritional challenge test in intervention studies is expected to demonstrate subtle improvements of phenotypic flexibility, thereby enabling substantiation of nutritional health effects.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-015-0459-1) contains supplementary material, which is available to authorized users.

Background: A key feature of metabolic health is the ability to adapt upon dietary perturbations. Recently, it was shown that metabolic challenge tests in combination with the new generation biomarkers allow the simultaneous quantification of major metabolic health processes. Currently, applied challenge tests are largely non-standardized. A systematic review defined an optimal nutritional challenge test, the "PhenFlex test" (PFT). This study aimed to prove that PFT modulates all relevant processes governing metabolic health thereby allowing to distinguish subjects with different metabolic health status. Therefore, 20 healthy and 20 type 2 diabetic (T2D) male subjects were challenged both by PFT and oral glucose tolerance test (OGTT). During the 8-h response time course, 132 parameters were quantified that report on 26 metabolic processes distributed over 7 organs (gut, liver, adipose, pancreas, vasculature, muscle, kidney) and systemic stress.

Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7a-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation.

Background:Recent evidence suggests that the gut microbiota plays an important role in human metabolism and energy homeostasis and is therefore a relevant factor in the assessment of metabolic health and flexibility. Understanding of these host–microbiome interactions aids the design of nutritional strategies that act via modulation of the microbiota. Nevertheless, relating gut microbiota composition to host health states remains challenging because of the sheer complexity of these ecosystems and the large degrees of interindividual variation in human microbiota composition.Methods:We assessed fecal microbiota composition and host response patterns of metabolic and inflammatory markers in 10 apparently healthy men subjected to a high-fat high-caloric diet (HFHC, 1300 kcal/day extra) for 4 weeks. DNA was isolated from stool and barcoded 16S rRNA gene amplicons were sequenced. Metabolic health parameters, including anthropomorphic and blood parameters, where determined at t=0 and t=4 weeks.Results:A correlation network approach revealed diet-induced changes in Bacteroides levels related to changes in carbohydrate oxidation rates, whereas the change in Firmicutes correlates with changes in fat oxidation. These results were confirmed by multivariate models. We identified correlations between microbial diversity indices and several inflammation-related host parameters that suggest a relation between diet-induced changes in gut microbiota diversity and inflammatory processes.Conclusions:This approach allowed us to identify significant correlations between abundances of microbial taxa and diet-induced shifts in several metabolic health parameters. Constructed correlation networks provide an overview of these relations, revealing groups of correlations that are of particular interest for explaining host health aspects through changes in the gut microbiota.