OC 29.1 - Fibrinogenγ390-396A protects against high fat diet-induced obesity and MASLD by altering glycine metabolism

Background: Obesity (i.e., body mass index >30) is a significant risk factor for numerous diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease. We have previously documented increased deposition of extravascular fibrin(ogen) in obese adipose tissues and liver. These fibrin(ogen) deposits colocalize with pro-inflammatory macrophages that drive obesity development. Consistently, mice expressing fibrinogen with a mutation in the binding site for macrophages (Fgg390-396A mice) are protected from diet-induced obesity (DIO) and associated metabolic pathologies.

Aims: Determine the molecular mechanisms by which fibrinogen-macrophage interaction drives DIO and metabolic sequelae.

Methods: Metabolite changes in plasma from low-fat diet (LFD)- or high fat diet (HFD)-fed FggWT and Fgg390-396A mice were analyzed by NMR-based metabolomics. FggWT and Fgg390-396A mice were challenged with HFD with and without glycine supplementation to determine the impact of elevated circulating glycine levels on the development of HFD-induced sequelae and coagulation function.

Results: NMR-based metabolomics revealed distinct diet and genotype signatures in HFD-fed FggWT and Fgg390-396A mice. Of particular interest was significantly higher circulating levels of glycine observed specifically in HFD-fed Fgg390-396A mice that correlated with protection from DIO and metabolic syndrome. Supporting a Fgg390-396A-glycine functional axis, hepatic expressions of Shmt1 and Shmt2, which regulate the conversion between serine and glycine, were increased in HFD-fed Fgg390-396A mice. More notably, glycine supplementation in the drinking water was protective against DIO and MASLD in HFD-fed FggWT mice, mimicking results observed in HFD-fed Fgg390-396A mice. Interestingly, a reciprocal relationship between circulating glycine and coagulation was observed as wildtype mice given glycine supplementation displayed reduced fibrinogen expression and thrombin generation as early as 4 weeks after treatment.

Conclusion(s): Our study identifies molecular mechanisms by which fibrinogen regulates HFD-induced metabolic pathologies through glycine metabolism. Moreover, our finding that glycine supplementation reduces fibrinogen expression and thrombin generation suggests a novel mechanism by which metabolic changes regulate hemostatic/thrombotic potential.