Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice

Skoug, Cecilia; Holm, Cecilia; Duarte, João M. N.

doi:10.1016/j.jlr.2022.100195

Cited by 14 publications

(32 citation statements)

References 59 publications

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“…Our previous work suggests that levels of bioactive lipids are modified in aged HSL−/− mice, when compared to littermate controls (Skoug et al, 2022), which could result in functional defects on, for example, the regulation of CBF. We measured eicosanoid and endocannabinoid profiles in the hippocampus and cortex of mice of the three genotypes after exposure to either CD or HFD (Figure 7).…”

Section: Hsl Deletion Shifts Brain Lipid Profilesmentioning

confidence: 99%

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

Skoug,

Rogova,

Spégel

et al. 2024

Journal of Neurochemistry

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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.

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Section: Hsl Deletion Shifts Brain Lipid Profilesmentioning

confidence: 99%

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

Skoug,

Rogova,

Spégel

et al. 2024

Journal of Neurochemistry

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“…First, the free cholesterol pool in the cytosol is related to the action of the hormone-sensitive lipase/cholesteryl esterase (HSL), encoded by the LIPE gene, which is responsible for hydrolyzing cholesteryl esters located in lipid droplets 53 . HSL protein and its enzymatic activity have been detected in the mouse brain at neuronal synapses 54 . It was then described that the proteins StAR and TSPO may be respectively involved in the delivery of cholesterol and its transport from the outer membrane to the inner membrane of mitochondria (reviewed in Selvaraj et al, 2018 55 ).…”

Section: Discovery and Evidence Of The Regulatory Loop Between Pregne...mentioning

confidence: 99%

“…54 HSL protein and its enzymatic activity have been detected in the mouse brain at neuronal synapses. 55 The proteins StAR and TSPO were described to be respectively involved in the delivery of cholesterol and its transport from the outer membrane to the inner membrane of mitochondria. 56 StAR mRNA and protein were detected in brain glial and neuronal cells and co-localization with P450scc was observed in the mouse and human cerebral cortex.…”

Section: The Actors Of Brain Pregnenolone Productionmentioning

confidence: 99%

“…HSL has been reported at neuronal synapses with a wide distribution within the mouse brain and has been proposed to play a key role in the neuroactive lipid homeostasis related to normal brain function. 55 Mitochondrial P450scc enzyme (CYP11A1) is the second target for CB1-mediated pregnenolone increase. P450scc is responsible for the initiation of steroidogenesis with the conversion of cholesterol to pregnenolone.…”

Section: How Does the Preg-cb1 Regulatory Loop Work?mentioning

confidence: 99%

“…The first involves the availability of free cholesterol required for steroidogenesis with the increase of HSL responsible for the hydrolysis of cholesterol esters. HSL has been reported at neuronal synapses with a wide distribution within the mouse brain and has been proposed to play a key role in the neuroactive lipid homeostasis related to normal brain function 55 . Mitochondrial P450scc enzyme (CYP11A1) is the second target for CB1‐mediated pregnenolone increase.…”

Section: Preg‐cb1r Loop In Homeostasis Prospectivementioning

confidence: 99%

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Cross‐talk between neurosteroid and endocannabinoid systems in cannabis addiction

Raux

Vallée

2022

J Neuroendocrinology

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High-fat and High-sucrose Diet-induced Hypothalamic Inflammation Shows Sex Specific Features in Mice

De Paula,

Simões,

Garcia-Serrano

et al. 2024

Neurochem Res

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Hypothalamic inflammation underlies diet-induced obesity and diabetes in rodent models. While diet normalization largely allows for recovery from metabolic impairment, it remains unknown whether long-term hypothalamic inflammation induced by obesogenic diets is a reversible process. In this study, we aimed at determining sex specificity of hypothalamic neuroinflammation and gliosis in mice fed a fat- and sugar-rich diet, and their reversibility upon diet normalization. Mice were fed a 60%-fat diet complemented by a 20% sucrose drink (HFHSD) for 3 days or 24 weeks, followed by a third group that had their diet normalized for the last 8 weeks of the study (reverse diet group, RevD). We determined the expression of pro- and anti-inflammatory cytokines, and of the inflammatory cell markers IBA1, CD68, GFAP and EMR1 in the hypothalamus, and analyzed morphology of microglia (IBA-1+ cells) and astrocytes (GFAP+ cells) in the arcuate nucleus. After 3 days of HFHSD feeding, male mice showed over-expression of IL-13, IL-18, IFN-γ, CD68 and EMR1 and reduced expression of IL-10, while females showed increased IL-6 and IBA1 and reduced IL-13, compared to controls. After 24 weeks of HFHSD exposure, male mice showed a general depression in the expression of cytokines, with prominent reduction of TNF-α, IL-6 and IL-13, but increased TGF-β, while female mice showed over-expression of IFN-γ and IL-18. Furthermore, both female and male mice showed some degree of gliosis after HFHSD feeding for 24 weeks. In mice of both sexes, diet normalization after prolonged HFHSD feeding resulted in partial neuroinflammation recovery in the hypothalamus, but gliosis was only recovered in females. In sum, HFHSD-fed mice display sex-specific inflammatory processes in the hypothalamus that are not fully reversible after diet normalization.

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Hormone-sensitive lipase is localized at synapses and is necessary for normal memory functioning in mice

Cited by 14 publications

References 59 publications

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

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

Cross‐talk between neurosteroid and endocannabinoid systems in cannabis addiction

High-fat and High-sucrose Diet-induced Hypothalamic Inflammation Shows Sex Specific Features in Mice

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