Apelin-driven metabolic ratios reflect post-stroke recovery in mice

Visceral fat gain and the progressive onset of metabolic disorders precipitate stroke risk and prompt the middle-aged population to cognitive decline. Preclinical research has recently focused on total apelin, a neuroprotective peptide whose cerebral action after release in plasma by adipose tissue remains elusive. The ratio between plasma apelin and lipids is suspected to influence prognosis in patients with cardiovascular diseases. This study challenged ratios of plasma apelin to cholesterol or glucose in reflecting post-stroke recovery of mature adult mice after a 6-month high-fat diet (HFD). Mice under HFD developed overweight (+10%, p < 0.001), hyperglycemia (21%, p < 0.001) and hypercholesterolemia (+68%, p < 0.001). Plasma apelin decreased with age in all mice (F_2,360 = 35.94, p < 0.001), but a 30-min middle cerebral artery occlusion (MCAO) induced a 27% drop in plasma apelin (p < 0.01) in HFD-fed mice only, as well as a higher acute mortality (29%) than in normal diet (ND)-fed mice (19%). Ten days after MCAO, apelin levels normalized in HFD-fed mice, but were still decreasing in ND-fed mice (p < 0.01). However, high pre-stroke ratios revealed an upregulation of brain apelin receptor expression in these mice, that was lost in metabolically disturbed mice displaying lower ratios. This was functionally confirmed since mice with higher pre-stroke ratios displayed significantly better locomotor and cognitive performances, as validated by ROC analysis (AUC = 0.85). This study highlights pre-stroke ratios of plasma apelin to cholesterol or glucose as potential new biomarkers of post-stroke recovery.