Modulation of bile acid receptors FXR and TGR5 for enhanced GLP-1 release
This research explores inhibiting FXR to enhance GLP-1 secretion via TGR5 activation, improving metabolic parameters in obesity treatment. Potential synergy with GLP-1 receptor agonists offers a novel combinatory approach for metabolic syndrome.
Overview
This research focuses on modulating bile acid receptors FXR and TGR5 to stimulate the release of glucagon-like peptide-1 (GLP-1), a hormone that plays a crucial role in glucose metabolism and energy expenditure. By inhibiting FXR, the composition of bile acids shifts, increasing the levels of secondary bile acids that act as potent agonists for TGR5. This activation enhances GLP-1 secretion from enteroendocrine L-cells, potentially improving glucose tolerance and insulin sensitivity in obese individuals. Additionally, this approach could synergize with existing GLP-1 receptor agonists, offering a promising combinatory treatment for obesity and metabolic syndrome.
Technical specifications
- FXR Inhibition: FXR is a nuclear receptor activated by bile acids, regulating metabolic pathways. Inhibition alters bile acid composition to increase secondary bile acids which activate TGR5.
- TGR5 Activation: TGR5 is a G-protein coupled receptor that, when activated by secondary bile acids, promotes GLP-1 secretion and energy expenditure.
- GLP-1 Secretion: Enhanced GLP-1 secretion improves glucose metabolism and supports weight loss, addressing key obesity treatment goals.
- Preclinical Validation: Gly-MCA, a high-affinity FXR inhibitor, has shown efficacy in reversing diet-induced obesity and insulin resistance in animal models, with ongoing screening of other amino acid-conjugated fatty acids for improved efficacy.
Technology readiness level
The technology is at a Technology Readiness Level of 4, indicating that it has been validated in laboratory settings with ongoing preclinical evaluations in animal models to further assess efficacy and potential applications.
About Penn State University
Penn State University is a comprehensive public land‑grant research university with a large multi‑campus footprint across Pennsylvania. Industry engages through a research and technology park adjacent to the flagship campus that houses corporate R&D, co‑located labs, and flexible collaboration space, as well as a statewide extension network that enables field testing, demonstration, and workforce reach. Integration with a major hospital system supports clinical translation, and an applied research laboratory fosters mission‑driven partnerships with government and industry sponsors. Research is supported by competitive federal funding from agencies such as NSF, NIH, DOE, USDA, DoD, and NASA. A dedicated technology transfer office manages IP, licensing, and startup formation to accelerate commercialization.
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