Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome.

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

Adipocyte NCoR Knockout Decreases PPARγ Phosphorylation and Enhances PPARγ Activity and Insulin Sensitivity

Johan Auwerx, Hiroyasu Yamamoto

Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.

2011

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

Mitsunori Nomura

EPFL2013