The Bile Acid Receptor FXR is Necessary for Metabolic Improvements Associated with Bariatric Surgery
6/10/2012 12:00:00 PM
6/10/2012 2:00:00 PM
, CHRISTOFFER CLEMMENSEN, HILARY E. WILSON-PEREZ, APRIL M. HALLER, ANDRYI MYRONOVYCH, ROHIT KOHLI, DARLEEN A. SANDOVAL, STEPHEN C. WOODS, RANDY J.. SEELEY,
In addition to facilitating digestion, bile acids function as signaling molecules involved in the regulation of metabolism. Both clinical and rodent studies find that bile acid metabolism is altered after bariatric surgery. Consistent with this, we find that vertical sleeve gastrectomy (VSG) leads to a 33% increase in plasma bile acids in mice (p< 0.05). Bile acids bind to and activate the nuclear receptor FXR, to regulate the gene expression. We hypothesized that FXR signaling contributes to metabolic improvements pursuant to VSG. To test this, we performed VSG or sham surgery in DIO FXR knockout mice (KO) and wild-type (WT) littermate controls. We found that the effect of the surgery on food intake (p< 0.01), body weight (p< 0.05), and glucose tolerance (p< 0.01) depended on genotype. Among WT mice, weight loss was initially achieved by reductions in caloric intake. However food intake increased over time, so that by 6 weeks daily food intake of VSG mice was not different than sham controls. The critical distinction, relative to dieting alone, is that VSG animals did not overeat at later time points to compensate for the initial caloric deficit and, as a result, weight-loss was maintained. At 8 weeks post-surgery, WT VSG mice had consumed 16% fewer total calories (p< 0.001) and weighed 22% less (p< 0.001) than WT shams. Among KO mice, VSG also elicited initial weight loss and acute reduction in caloric intake. In contrast to WT mice however, food intake recovered quickly and, beginning at 4 weeks KO VSG mice ate 15%
than KO shams. As a result, by 8 weeks KO VSG mice had fully recovered the weight loss, and consumed the same number of total calories as KO shams. With respect to glucose tolerance, we observed a 35% reduction in the area under the glucose concentration: time curve (AUC, p< 0.001) in WT VSG vs. WT shams. In contrast, there was no difference in AUC between KO VSG and KO shams. Together, these data support that bile acid signaling via FXR contributes to the beneficial effects of this bariatric surgery.
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