Impact of Genetically Induced Metabolic Syndrome on the Outcomes of Photothrombotic Stroke in Leptin-Deficient and Leptin Receptor-Deficient Mice

Diabetes and obesity are associated with poorer outcomes after ischemic stroke; however, it remains unclear whether this results from increased neuronal susceptibility to injury or from vascular dysfunction induced by metabolic syndrome. To minimize the contribution of vascular factors, we used a model of photoinduced thrombosis (PT) in cortical vessels, which generates lesions of reproducible size and is less dependent on collateral blood flow. PT was induced in wild-type (WT) mice, as well as in ob/ob (leptin-deficient) and db/db (leptin receptor-deficient) mice. Magnetic resonance imaging (MRI) revealed that PT produced comparable infarct volumes in all mouse groups. Several genes associated with inflammation and activation of microglia and macroglia in the peri-infarct area (Cst7, Ccl3, Tlr2, Gfap) exhibited similar expression patterns across all three mouse strains, while transcriptional response to cerebral ischemia of Tnfa, Cxcl9, Il6, Cox2, Mmp3, and Bdnf genes depended on the genotype. Overall, despite individual differences in the expression profiles of certain genes, disruption of leptin signaling (whether due to leptin deficiency or leptin receptor deficiency) caused no genotype-specific exacerbation of stroke-induced injury. Assessment of post-stroke neurological deficits revealed substantial differences in absolute scores between WT and ob/ob or db/db mice, attributable to baseline disparities in body weight and motor activity. In db/db mice, normalization of post-stroke neurological status scores to pre-injury values revealed a more pronounced relative functional decline compared to ob/ob mice, suggesting impairments in early compensatory mechanisms and an important role of leptin signaling in neuroplasticity rather than in the extent of acute neuronal damage. Thus, under conditions that minimize vascular complications, neither leptin deficiency nor leptin receptor deficiency exacerbated acute ischemic brain damage or neuroinflammation.