Biology subjects

Duarte, J. M. N.

Publications and source records attributed to Duarte, J. M. N..

3 recordsLinked to original sources

bioRxiv2021

Central hormone-sensitive lipase is located at synapses and is necessary for normal memory performance in mice

Hormone-sensitive lipase (HSL) is mainly present in the adipose tissue where it hydrolyses diacylglycerol. Although brain expression of HSL has been reported, its presence in different cellular compartments is uncertain, and its role in regulating brain lipid metabolism remains hitherto unexplored. We propose that HSL has a role in regulating the availability of bioactive lipids necessary for adequate neuronal function. Therefore, we tested the hypothesis that dampening HSL activity leads to brain dysfunction. We found HSL protein and activity throughout all the mouse brain, localised in neurons and especially enriched in synapses. HSL null mice were then analysed using a battery of behavioural tests. Relative to wild-type littermates, HSL null mice showed impaired short- and long-term memory, but preserved exploratory behaviours. Molecular analysis of the cortex and hippocampus showed increased expression of genes involved in glucose utilization in the hippocampus but not cortex of HSL null mice compared to controls. Lipidomics analyses indicated an impact of HSL deletion on the profile of bioactive lipids, including endocannabinoids and eicosanoids that are known to modulate neuronal activity, cerebral blood blow and inflammation processes. Accordingly, mild increases in expression of pro-inflammatory cytokines suggest low grade inflammation in HSL null mice compared to littermates. We conclude that HSL has a homeostatic role in maintaining pools of lipids that are needed for brain function. It remains to be tested, however, whether the recruitment of HSL for the synthesis of these lipids occurs during increased neuronal activity, or whether HSL participates in neuroinflammatory responses.

neuroscience↗

bioRxiv2021

Cognitive impairment and metabolite profile alterations in the hippocampus and cortex of male and female mice exposed to a fat and sugar-rich diet are normalized by diet reversal

Diabetes impacts on brain metabolism, structure and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar, and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. To test this hypothesis, mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by 1H magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed a HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex, but were more distinct in the former. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine, N-acetylaspartate, creatine and choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. We conclude that cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.

neuroscience↗

bioRxiv2020

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet

The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for 7 days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.

neuroscience↗