Role of the bile acid membrane receptor TGR5 in macrophages and metabolism

Activation of the bile acid responsive G protein-coupled receptor TGR5 improves metabolic homeostasis via induction of energy expenditure and release of glucagon-like peptide-1 (GLP-1). The goal of my PhD work was to explore the role of macrophage TGR5 with respect to inflammation and to evaluate its impact on chronic low-grade inflammatory and metabolic disorders, such as atherosclerosis and insulin resistance. In the first part of this work, we have focused on the role of TGR5 in the progression of atherosclerotic lesions. I showed that activation of TGR5 in macrophages by 6"-ethyl-23(S)-methyl-cholic acid (S-EMCA, INT-777), a semi-synthetic bile acid, inhibits pro-inflammatory responses via a cAMP-NF-!# pathway. Furthermore, INT-777 treatment of chimeric Ldlr knockout mice that were transplanted with bone marrow from either Tgr5 wild-type or Tgr5 knockout mice, revealed that TGR5 in leukocytes largely contribute to the protective effects on atherosclerotic lesion formation. In the second part of this work, I have determined the function of TGR5 in macrophage polarization and evaluated the relative contribution of macrophage TGR5 in the onset of diet-induced insulin resistance. I demonstrated that deficiency of TGR5 results in exacerbated insulin resistance in diet-induced obesity (DIO) mice with severe impairment of insulin responsiveness in adipose tissue. This was associated with an increase in M1 macrophages and a reduction of M2 macrophages in adipose tissue of Tgr5 knockout mice. In line with this, TGR5 activation by INT-777 in DIO mice increased M2 macrophages, attenuated adipose tissue inflammation and improved insulin resistance. Taken together, the research that is described in this thesis reveals a significant immune modulatory function of TGR5, which has a major impact on the prevention of atherosclerosis and insulin resistance in mouse models. Future studies in humans will be required to underscore the importance of TGR5 as a potential target to counteract the chronic low-grade inflammation that goes hand-in hand with many disorders of the metabolic syndrome.