Page 154 - Human Bile Acid Metabolism: a Postprandial Perspective

Chapter 8
TGR5 and energy expenditure
Preclinical data
One of the potential targets of extraintestinal bile acid signalling is the increased energy expenditure leading to reduced weight gain seen in animal models of obesity (figure 3). Watanabe and colleagues1 showed that dietary supplementation of cholic acid in mice prevents and reverses high-fat diet-induced weight gain via Tgr5-dependent energy expenditure in muscle and brown adipose tissue (BAT). Quantitative real-time PCR analysis of BAT in these mice showed upregulation of key genes in energy expenditure such as peroxisome-proliferator-activated receptor γ coactivator 1α (Pgc1α) and type II iodothyronine deiodinase (Dio2). Increased transcription of these genes induces upregulation of uncoupling protein 1 (Ucp1) in mitochondria, which diverts electron gradients towards thermogenesis instead of ATP production. The effect of cholic acid supplementation on bodyweight was lost in Dio2-knockout mice that were fed a high-fat diet.
In-vitro stimulation with either bile acids or a specific TGR5 agonist of BAT cells isolated from mice that were either fed chow or a high-fat diet increased transcription and activity of DIO2 and UCP1 through TGR5 activation.1 In- vivo studies with other natural and semisynthetic selective TGR5 agonists have confirmed the observed effects on energy expenditure and bodyweight.2,3 Treatment with colestilan, a second-generation bile acid sequestrant, had opposing effects on parameters of bile acid signalling—for example, decreasing activation of the bile acid receptor FXR—but mimicking the effects of cholic acid supplementation on the bile acid pool and energy expenditure in diet-induced obese mice.62 By contrast, bodyweight of Tgr5–/– mice fed an isocaloric diet is similar to that of wild- type mice.2,4,63
Plasma bile acid concentrations are consistently increased in animal models of RYGB surgery.64 RYGB leads to weight loss through increased energy expenditure and changes in gastrointestinal physiology, which has been detected by pair-feeding experiments and indirect calorimetry in rodents.65,66 Both the resting energy expenditure and the postprandial increase in thermogenesis were significantly increased in mice that had RYGB surgery compared with mice that had not undergone surgery; these changes might be due to increased TGR5 activation due to increased plasma bile acid concentrations, but other explanations are possible. 67
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