Temporal Dissociation of Impaired Glucose Tolerance, Adipose Lipid Remodeling and Endothelial Dysfunction in Aorta After <scp>HFD</scp> Withdrawal

Glucose intolerance and endothelial dysfunction are metabolic syndrome hallmarks induced by fat load, but their reversibility is not well explored. Here, we characterize the effects of high-fat diet (HFD) withdrawal on systemic glucose tolerance, endothelial function in aorta (thoracic, TA and abdominal, AA), lipid unsaturation of perivascular adipose tissue (PVAT), and mRNA expression profile. We studied the early and late effects of diet change on C57BL/6J mice after 8 weeks of HFD feeding (60 kcal% of fat with 1% of cholesterol) by implementing multimodal functional (in vivo MRI), spectroscopic (Raman spectroscopy), and molecular (RT-qPCR) characterization of aortas and PVATs. As soon as 1 week after HFD withdrawal, glucose tolerance was normalized and accompanied by the reversal of lowered Scd1 gene expression in PVAT and lipid unsaturation index in PVAT of AA, but not of TA. In contrast, impaired acetylcholine-induced vasodilation in aorta, implicating endothelial dysfunction, was only partially reversed 1 week after HFD withdrawal, whereas full restoration occurred after 6 weeks, with slightly earlier recovery in TA compared to AA. Delayed reversal of endothelial dysfunction in aorta after HFD withdrawal was associated with transcriptomic alterations, indicating downregulation of soluble guanylate cyclase signaling, compensatory changes in insulin signaling, and changes in adipokines expression in PVAT, but not in aorta itself. In summary, HFD withdrawal resulted in early restoration of glucose tolerance, and PVAT lipid unsaturation determined by Scd1 that was temporarily dissociated from the reversal of endothelial dysfunction in the aorta possibly due to altered PVAT function featured by impaired guanylate cyclase signaling pathway.