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

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.

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

Mitsunori Nomura

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.

EPFL2013

Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway

Johan Auwerx

Impairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation. In this study we have analyzed the effects of agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARalpha agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation. In contrast, the synthetic PPARgamma agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct. In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARalpha activation and requires signaling through the ERK1/2 signaling pathway.

2003

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

Mitsunori Nomura

EPFL2013