Kelley, E. E. | bioRxiv Science

bioRxiv2026

A Regionally Inspired West Virginia Obesogenic Diet Induces Fat Accretion and Metabolic Dysfunction While Identifying Sex Disparity

Obesity prevalence continues to rise in the United States, with a disproportionate burden falling to West Virginia. To investigate the metabolic effects of region-specific dietary patterns, we developed the West Virginia Obesogenic Diet (WV-OD), a compositionally defined rodent diet based on nutritional analyses of meals consumed by obese individuals in the state. The WV-OD closely mirrors the macronutrient profile of the average American diet while incorporating regional features such as a greater sodium level and significantly less fiber. We compared the metabolic effects of the WV-OD to a matched control diet (WV-CD) and to a widely used high-fat diet (HFD, 60% of calories derived from fat) in male and female C57BL/6J mice. After 19 weeks, WV-OD-fed males exhibited weight gain and adiposity comparable to HFD-fed counterparts, along with glucose intolerance and hepatic triglyceride accumulation confirming the obesogenic and metabolically disruptive properties of the WV-OD. Unlike HFD-fed mice, WV-OD-fed males also displayed elevated circulating cholesterol and cholesterol esters without corresponding increases in hepatic total cholesterol. When compared to the HFD, the WV-OD did not increase uric acid or xanthine oxidoreductase (XOR) content of liver or circulation; however, both males and females on the WV-OD demonstrated trends towards elevated plasma uric acid. Interestingly, while exhibiting a similar caloric intake on either diet, the WV-OD females did not demonstrate significant fat accretion or metabolic dysfunction compared to females subjected to the 60% HFD. In toto, these findings: 1) establish the WV-OD as a regionally-grounded, yet broadly representative tool for modeling diet-induced obesity and metabolic dysfunction, 2) offer a physiologically relevant alternative to extreme-fat dietary models in preclinical research and 3) highlight sex-based differences in response to diet-induced obesity.

physiology↗

bioRxiv2025

Liver-Derived, Circulating Xanthine Oxidoreductase Drives Vascular Impairment Associated with Inhalation of Ultrafine Particulates.

Inhalation of ultrafine particles (UFP) mediates systemic vascular impairment which is, in part, driven by elevated rates of oxidant generation. One significant source of oxidant production in the vascular compartment is the purine catabolizing enzyme, xanthine oxidoreductase (XOR). However, mechanisms linking XOR and/or endothelial glycosaminoglycan (GAG)-sequestered XOR to vessel dysfunction allied to UFP inhalation remain underexplored. Based on known interactions between UFP and the liver, we hypothesized that exposure could lead to hepatic release of XOR to the circulation which subsequently contributes to vascular impairment. Utilizing our murine hepatocyte-specific XOR knockout (XORHep-/-) model (loss of function) in conjunction with reintroducing exogenous XOR (restoration of function) we demonstrate a specific role for liver-derived XOR in the pathogenesis of UFP-induced vascular impairment. Exposure of mice as well as in vitro exposure of hepatocytes to our model UFP, nano titanium dioxide (nTiO2) results in the upregulation and active release of XOR. Drinking water supplemented with the XOR inhibitor febuxostat or nitrite (NaNO2-) partially prevented nTiO2-induced impairment of vascular reactivity. Interestingly, nitrite appears to cause a down-regulation of hepatic XOR. XORHep-/- mice were partially protected against both impairment of endothelial dependent dilation and augmented angiotensin II constriction. To further demonstrate the role of circulating XOR in nTiO2-induced impairment of vessel reactivity, XORHep-/- mice had circulating XOR restored by i.v. injection prior to exposure, which eliminated the protection of the hepatic knockout. It is important to note that acute restoration of intraluminal XOR in isolated vessels did not alter endothelial-dependent dilation or angiotensin II constriction. As such, we interrogated potential downstream mediators of XOR effects on endothelial function and found a decrease in the repressive trimethylation of lysine 9 on histone 3. Together these findings demonstrate that circulating XOR is a key contributor to endothelial dysfunction caused by UFP exposure. However, the impairment is not acute in nature and might involve epigenetic-mediated alterations in gene expression.

physiology↗