Role of apelin-13 in ischemic stroke under high-fat diet-induced metabolic disturbances at middle- age

Abstract

Introduction: Visceral fat gain and the progressive onset of metabolic disorders in middle-aged mice induce alteration of the cerebral vascular tree in association with mild cognitive impairment. This precipitates stroke risk and might prompt the middle-aged population to cognitive decline. In this context, an endogenous peptide named apelin-13 and its receptor APJ are suspected to link metabolic disorders at middle age to the consequences of ischemic stroke on brain tissue, as well as vasomotor and cognitive functions. Apelin-13 induces neuroprotection after experimental ischemic stroke, but this action has not been examined under metabolic disturbances. The aim of our study is to evaluate the role of apelin-13 as a new therapeutic target in ischemic stroke under high-fat diet-induced metabolic disturbances at middle-age. Methods: C57Bl/6 mice were fed for 6 months with normal diet (ND) or high-fat diet (HFD) before 30-minute middle cerebral artery occlusion (MCAO). Metabolic parameters, as well as circulating apelin-13 levels were evaluated every 3 months before MCAO. APJ brain expression and plasmatic apelin rate were assess at acute phase (24h post-stroke) and after behavioral (motor and cognitive) evaluation at chronic phase (10 days after MCAO). Results: Mice under HFD developed overweight, hyperglycemia and hypercholesterolemia. Plasmatic apelin slowly decreased with age and was different between overweight and lean mice, but not between HFD and ND. The onset of MCAO under HFD induced 49% higher mortality than under ND. At acute phase, mice under HFD had a 25% decreased plasmatic apelin rate whereas mice under ND had a 2.5% of reduction. APJ brain expression in HFD mice was 59% reduced compared to ND. After 10 days, worsened behavioral impairment was observed in HFD mice compared to ND mice. Plasmatic apelin levels were reduced whatever the diet. Discussion: These first results highlight the contribution of the apelinergic system to the influence of metabolic disturbances on stroke severity, that should be considered in therapeutic studies.