Key result
AhR deletion protected male mice from high-fat diet-induced dyslipidaemia, weight gain, and inflammatory processes, and attenuated endothelial dysfunction by improving eNOS/NO signalling.
Why the study?
Whether vascular aryl hydrocarbon receptors are activated in obesity, or exert protective or harmful effects on vascular function in obesity, was unknown.
Does AhR deletion or antagonism prevent high-fat diet-induced vascular dysfunction in mice?
Does AhR deletion or antagonism prevent high-fat diet-induced vascular dysfunction in mice?
AhR deletion attenuates high-fat diet-induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling, suggesting AhR as a potential therapeutic target.
AhR activation may promote obesity-linked vascular dysfunction in mice; leaves open therapeutic targeting in patients pending human studies.
Background and Purpose Metabolic and vascular dysfunction are common features of obesity. Aryl hydrocarbon receptor (AhR) regulates lipid metabolism and vascular homeostasis, but whether vascular AhR are activated in obesity or have a protective and/or harmful effects on vascular function in obesity are unknown. Our study addresses whether AhR activation contributes to obesity‐associated vascular dysfunction and the mechanisms involved in these AhR effects. Experimental Approach Male AhR KO ( Ahr −/− ) and WT mice were fed either control or a HF (high‐fat) diet for 10 weeks. Metabolic and inflammatory parameters were measured in serum and adipose tissue. Vascular reactivity (isometric force) was evaluated using a myography. Endothelial NOS (eNOS) and AhR protein expression was determined by western blot, Cyp1A1 and Nos3 gene expression by RT‐PCR and.NO production was quantified by DAF fluorescence. Key Results HF diet increased total serum HDL and LDL, as well as vascular AhR protein expression and proinflammatory cytokines in the adipose tissue. HF diet decreased endothelium‐dependent vasodilation. AhR deletion protected mice from HF diet‐induced dyslipidaemia, weight gain and inflammatory processes. HF diet‐induced endothelial dysfunction was attenuated in Ahr −/− mice. Vessels from Ahr −/− mice exhibited a greater NO reserve. In cultured endothelial cells, lysophosphatidylcholine (LPC) a major component of LDL and oxidized LDL [oxLDL]) reduced Nos3 gene expression and NO production. Antagonism of the AhR inhibited LPC effects on endothelial cells and induced decreased endothelium‐dependent vasodilation. Conclusion and Implications AhR deletion attenuates HF diet‐induced dyslipidaemia and vascular dysfunction by improving eNOS/NO signalling. Targeting AhRs may prevent obesity‐associated vascular dysfunction.
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Silva et al. (2022) studied Obesity-associated vascular dysfunction. AhR deletion (Ahr-/-) vs. Wild-type (WT) mice was evaluated on Vascular dysfunction, dyslipidaemia, weight gain, and inflammatory processes. AhR deletion protected male mice from high-fat diet-induced dyslipidaemia, weight gain, and inflammatory processes, and attenuated endothelial dysfunction by improving eNOS/NO signalling.