Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure

Background: Besides well-established roles of bile acids (BA) in dietary lipid absorption and cholesterol homeostasis, it has recently become clear that BA is also a biological signaling molecule. We have shown that strategies aimed at activating TGR5 by increasing the BA pool size with BA administration may constitute a significant therapeutic advance to combat the metabolic syndrome and suggest that such strategies are worth testing in a clinical setting. Bile acid binding resin (BABR) is known not only to reduce serum cholesterol levels but also to improve glucose tolerance and insulin resistance in animal models and humans. However, the mechanisms by which BABR affects glucose homeostasis have not been established. We investigated how BABR affects glycemic control in diet-induced obesity models. Methods and Findings: We evaluated the metabolic effect of BABR by administrating colestimide to animal models for the metabolic syndrome. Administration of BABR increased energy expenditure, translating into significant weight reduction and insulin sensitization. The metabolic effects of BABR coincide with activation of cholesterol and BA synthesis in liver and thermogenesis in brown adipose tissue. Interestingly, these effects of BABR occur despite normal food intake and triglyceride absorption. Administration of BABR and BA had similar effects on BA composition and thermogenesis, suggesting that they both are mediated via TGR5 activation. Conclusion: Our data hence suggest that BABR could be useful for the management of the impaired glucose tolerance of the metabolic syndrome, since they not only lower cholesterol levels, but also reduce obesity and improve insulin resistanc

BABR increase energy expenditure.

<p>Hematoxylin and eosin (HE) stained epWAT (A) and BAT (B) sections of C57BL/6J animals treated with control or HF diet when indicated combined with colestimide or CA as specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1</a>. Scale bar, 50 µm. (C) BAT analysis by transmission electron microscopy. (D) Averaged O₂ consumption (VO₂) and CO₂ production (VCO₂) as measured by indirect calorimetry in mice on the different diets as indicated. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

Bile acid composition in the enterohepatic organs and serum.

<p>Bile acid composition in the enterohepatic organs and serum of C57BL/6J fed with high fat diet (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>) after treatment with colestimide or CA. Undefined abbreviations are: G, glycol; T, tauro; CD, chenodeoxy; D, deoxy; H, hyo; HD, hyodeoxy; UD, ursodeoxy; L, litho; M, muri.</p

BA and BABR improve metabolic control in DIO C57BL/6J mice model.

<p>(A) Body weight, food intake and TG absorption (B) Liver, epididymal WAT (epWAT), and BAT weight change of C57BL/6J mice during 96 days on different diets. Ch stands for chow, F denotes HF diet, FCOL denotes HF diet+2.0% w/w colestimide and FB denotes HF diet+0.5% w/w CA. (C) Serum levels of TG, T-C, LDL-C, glucose and insulin in C57BL/6J mice on the indicated treatments. (D) Glucose levels during OGTT and IPITT in the different treatment groups (AUC is depicted in the inset). The OGTT were performed after an overnight fast after 9 weeks of administration. Glucose was administered by gavage at a dose of 2 g/kg. The IPITT were performed after 4 h fast after 10 weeks of administration. Insulin was injected at a dose of 0.75 U/kg. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

BA pool size and serum BA concentration in C57BL/6J mice.

<p>Ch denotes chow, F denotes HF diet, FCOL denotes HF diet+2% w/w colestimide and FB denotes HF diet+0.5% w/w CA as specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>.</p><p>Data are expressed as mean +/− SEM (n = 5–6).</p>A<p><i>P</i><0.05 versus F.</p>B<p><i>P</i><0.01 versus F.</p

Gene expression in liver, BAT, muscle and ileum.

<p>(A) mRNA expression levels of <i>Cyp7a1</i>, <i>Cyp8b1, Cyp27a1, Shp</i>, <i>Fxr</i>, <i>Pgc-1α</i>, <i>Pepck</i>, <i>G6Pase</i>, <i>Srebp-2</i>, HMG-CoA reductase, LDL-Receptor, <i>Pparα</i>, <i>Acc1</i> and <i>Scd1</i> were determined using quantitative RT-PCR in liver of C57BL/6J mice treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>. (B) mRNA expression levels of <i>D2</i>, <i>Pgc-1α</i> and <i>Ucp-1</i> in BAT. (C) <i>Pgc-1α</i> and <i>mCpt-1</i> in muscle. (D) <i>Fgf15</i> in ileum. Treatments and abbreviations are identical to those specified in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038286#pone-0038286-g001" target="_blank">Fig. 1A</a>. Mice were fasted 4 hours before sacrifice and tissue collection. Data are expressed as the mean +/− SEM (n = 5–6). * (<i>P</i><0.05) or ** (<i>P</i><0.01) versus F.</p

Changes in energy metabolism by BABR administration.

<p>Administration of BABR to animals leads to induction of bile acid synthesis and as a consequence a relative increase in CA and TCA. This translates into induced energy expenditure in brown adipose tissue, hence improving obesity and diabetes.</p

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P &lt; 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo