Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice

Abstract

EB, Yin DP. Activation of bile acid signaling improves metabolic phenotypes in high-fat diet-induced obese mice. Am J Physiol Gastrointest Liver Physiol 311: G286 -G304, 2016. First published June 23, 2016 doi:10.1152/ajpgi.00202.2016.-The metabolic benefits induced by gastric bypass, currently the most effective treatment for morbid obesity, are associated with bile acid (BA) delivery to the distal intestine. However, mechanistic insights into BA signaling in the mediation of metabolic benefits remain an area of study. The bile diversion () mouse model, in which the gallbladder is anastomosed to the distal jejunum, was used to test the specific role of BA in the regulation of glucose and lipid homeostasis. Metabolic phenotype, including body weight and composition, glucose tolerance, energy expenditure, thermogenesis genes, total BA and BA composition in the circulation and portal vein, and gut microbiota were examined. BD improves the metabolic phenotype, which is in accord with increased circulating primary BAs and regulation of enterohormones. BD-induced hypertrophy of the proximal intestine in the absence of BA was reversed by BA oral gavage, but without influencing BD metabolic benefits. BD-enhanced energy expenditure was associated with elevated TGR5, D2, and thermogenic genes, including UCP1, PRDM16, PGC-1␣, PGC-1␤, and PDGFR␣ in epididymal white adipose tissue (WAT) and inguinal WAT, but not in brown adipose tissue. BD resulted in an altered gut microbiota profile (i.e., Firmicutes bacteria were decreased, Bacteroidetes were increased, and Akkermansia was positively correlated with higher levels of circulating primary BAs). Our study demonstrates that enhancement of BA signaling regulates glucose and lipid homeostasis, promotes thermogenesis, and modulates the gut microbiota, which collectively resulted in an improved metabolic phenotype. bile acids; bile diversion; obesity; energy expenditure; gut microbiota; gastric bypass; mice

Bile acids and bariatric surgery

“…Ileal transposition, a procedure that interposes a segment of the distal ileum in a more proximal jejunal position, has been shown to improve insulin sensitivity and glucose tolerance (Culnan et al, 2010; B. P. Cummings et al, 2010; Ikezawa et al, 2012; Strader et al, 2009) in a number of genetic and diet-induced obesity/diabetic rodent models. Similar to the observed findings with ileal interposition, bile diversion operations (Flynn et al, 2015; Kohli et al, 2013b; Pierre et al, 2016; X. Zhang et al, 2015) result in complete diversion of bile from the upper GI tract to either the mid-jejunum (Goncalves et al, 2015; Kohli et al, 2013b) or ileum (Flynn et al, 2015); both of which are associated with not only significant elevations in circulating plasma bile acids but also improved glucose tolerance, insulin sensitivity, hypophagia, weight loss and resolution of hepatic steatosis.…”

“…This area requires intense investigation, and may require examination of the various pathways involved in bile acid clearance, or even examining the involvement of the microbiome in influencing bile acid homeostasis. In this regard, fecal bile acids have been reported as either decreased (Kohli et al, 2010) or unchanged (Kohli et al, 2013b; Pierre et al, 2016) after ileal interposition or bile diversion, respectively, while similar data in RYGB has shown conflicting results (Bhutta et al, 2015; J. V. Li et al, 2011). …”

Bile Diversion Improves Metabolic Phenotype Dependent on Farnesoid X Receptor (FXR)

“…The beneficial effects of bariatric surgery, such as Roux‐en‐Y gastric bypass and VSG, may be associated with delivery of BAs to the distal intestine and increases of circulating BAs that trigger downstream signaling pathways via the activation of BA receptors . Consistent with our previous report , current findings demonstrate that delivery of BAs to the distal intestine by BD improves metabolic phenotype in HFD‐fed WT mice. Mice lacking FXR diverged from WT mice with the following two contradictory characteristics: resistance to HFD‐induced obesity associated with increased PPARα and the development of hyperglycemia along with increased circulating total BAs and TbMCA.…”

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation

“…The milder disease and favorable metabolic profile of patients with lean NAFLD could be explained by the current findings. There is strong evidence that activation of BA signaling induces improvements in metabolic (glucose and lipid) phenotypes in murine models . Furthermore, in both humans and murine models, elevated BAs play a role in the metabolic improvements after bariatric surgery, including in type 2 diabetes, dyslipidemia, and NASH, even before significant weight loss .…”