Postprandial plasma bile acid responses in normal weight and obese subjects

Glicksman, C.; Pournaras, Dimitrios J.; Wright, Matthew; Roberts, Ruth E.; Mahon, David; Welbourn, Richard; Sherwood, Roy; Alaghband-Zadeh, J.; Roux, Carel W. le

doi:10.1258/acb.2010.010040

Cited by 81 publications

(75 citation statements)

References 7 publications

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“…Patients after bariatric surgery to correct for obesity have higher circulating levels of BAs, which are positively correlated with metabolic improvements (40,41). This latter observation was recently confirmed in obese patients, who have a decreased postprandial BA response in comparison with normal weight subjects (42). In contrast to this body of evidence that suggests that increasing BA levels benefit metabolic homeostasis, GW4064 decreased the expression levels of genes involved in energy expenditure in BAT, underscoring that these effects are not directly caused by FXR activation but rather are the consequence of reduced TGR5 activation subsequent to the reduction in the BA pool.…”

Section: Discussionmentioning

confidence: 73%

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

Watanabe

Horai

Houten

et al. 2011

Journal of Biological Chemistry

227

174

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We evaluated the metabolic impact of farnesoid X receptor (FXR) activation by administering a synthetic FXR agonist (GW4064) to mice in which obesity was induced by a high fat diet. Administration of GW4064 accentuated body weight gain and glucose intolerance induced by the high fat diet and led to a pronounced worsening of the changes in liver and adipose tissue. Mechanistically, treatment with GW4064 decreased bile acid (BA) biosynthesis, BA pool size, and energy expenditure, whereas reconstitution of the BA pool in these GW4064-treated animals by BA administration dose-dependently reverted the metabolic abnormalities. Our data therefore suggest that activation of FXR with synthetic agonists is not useful for long term management of the metabolic syndrome, as it reduces the BA pool size and subsequently decreases energy expenditure, translating as weight gain and insulin resistance. In contrast, expansion of the BA pool size, which can be achieved by BA administration, could be an interesting strategy to manage the metabolic syndrome.

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Section: Discussionmentioning

confidence: 73%

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

Watanabe

Horai

Houten

et al. 2011

Journal of Biological Chemistry

227

174

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show abstract

“…The relevance of our findings for man remains to be elucidated. However, it has been reported that obese subjects had a lower post-prandial bile acid response, relative to normal weight subjects (80). Furthermore, subjects that had previously undergone gastric bypass showed higher circulating bile acid levels, relative to both obese and severely obese objects.…”

Section: Discussionmentioning

confidence: 93%

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome

Liaset¹,

Qin

Jørgensen

et al. 2011

Journal of Biological Chemistry

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Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from dietinduced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1␣, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferatoractivated receptor ␤/␦ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.

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“…Indeed, relevant to obesity is the observation that bile salts act as 'nutrient signalling molecules' in a feed/fast cycle controlling the flow of absorbed molecules after meals. This could be of considerable interest if there was a postprandial reduced bile response in obese individuals as reported by Glicksman et al 1 FXR is essential in the feed/fast cycle and inhibition of glycolysis and may lower triglycerides by enhanced very-low-density lipoprotein production turnover and lipoprotein lipase activation. FXR also is implicated in the downregulation of hepatic fatty acid and triglyceride biosynthesis mediated by sterolregulatory-element-binding protein 1c.…”

mentioning

confidence: 89%

Bile salts and obesity

Crook

2010

Ann Clin Biochem

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Glicksman et al. 1 in this edition report a decreased postprandial bile acid response in obese individuals. Obesity is known to be associated with an increased incidence of gallstones and increased biliary cholesterol secretion. Jejunoileal bypass, which is sometimes used as a bariatric surgical procedure to treat morbid obesity, decreases pool sizes of bile salts, by increasing their turnover rates, while the rate of bile salt synthesis increases. 2 Four main bile acids are produced in humans. Two of these, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver. They are secreted in bile as sodium salts, conjugated with the amino acids glycine or taurine although some are conjugated with sulphate (primary bile salts). These in turn are converted by bacteria within the intestinal lumen to the secondary bile salts deoxycholate and lithocholate, respectively. Secondary bile salts are absorbed from the terminal ileum and colon and are re-excreted by the liver (enterohepatic circulation of bile salts). In the normal fasting state, serum CDCA predominates. The biliary canalicular secretion of bile salts is mediated mainly by the bile salt export pump.Serum total bile salt concentrations increase about 2-5-fold after meals, with a peak at about 60-90 min postprandially. Concentrations return to fasting levels over several hours. Hepatic extraction of these is highly efficient, meaning that bile salts are present at very low concentrations in the systemic circulation where they are highly protein-bound. Currently, the main clinical indication to measure serum bile salts is in the investigation of cholestasis of pregnancy. 3 Bile salts are far more than simply gastrointestinal detergents. They are also involved in cholesterol and fat soluble vitamin absorption as well as conferring resistance to intestinal bacterial overgrowth and regulation of the small intestine enzyme enteropeptidase. 4,5 Bile salts have more recently been shown to be important biochemical modulators and activate certain nuclear receptors such as preganane X, farnesoid X (FXR), vitamin D and also G protein coupled TGR5. The latter regulates in vivo glucagonlike peptide-1 and peptide YY secretion which enhance glucose tolerance and also energy expenditure in adipose tissue. Administration of bile salts to mice increased energy expenditure in brown adipose tissue and reduced insulin resistance and obesity. 6 -9 Bile salts are also implicated in cell signalling pathways, e.g. extracellular signal regulated kinases. Indeed, relevant to obesity is the observation that bile salts act as 'nutrient

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Postprandial plasma bile acid responses in normal weight and obese subjects

Abstract: The decreased postprandial bile acid response in obese subjects compared with normal weight subjects may partly explain the suboptimal GLP-1 and PYY responses and could affect appetite, glycaemic control and energy expenditure.

Cited by 81 publications

References 7 publications

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome

Bile salts and obesity

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