Genetic deletion of hormone‐sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet‐induced obesity on memory

Abstract Hormone‐sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet‐induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high‐fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild‐type mice. CBF was positively correlated with lectin‐stained vessel density. HSL deletion did not exacerbate HFD‐induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild‐type mice, and HSL deletion did not significantly aggravate HFD‐induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD‐induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet‐induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD‐induced neuroinflammation and memory dysfunction.