Biology subjects

Duarte, J. M. N.

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

8 recordsLinked to original sources

bioRxiv2025

Ultra-High Field 31P functional Magnetic Resonance Spectroscopy Reveals NAD+ Dynamics in Brain Energy Metabolism during Visual Stimulation.

We investigated dynamic changes in nicotinamide adenine dinucleotide (NAD{square}) metabolism in the human occipital lobe using ultra-high field 31P functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. Twenty-five healthy volunteers (mean age 24 {+/-} 4 years, 10 female) performed a visual task alternating between fixation and flashing checkerboard stimuli. 31P MRS spectra were acquired from a visual cortex voxel functionally localized by prior fMRI. Linear mixed-effects modelling revealed a significant reduction in NAD{square} concentrations during the first stimulation block, while no significant change was observed during the second block. No significant changes were observed for other high-energy phosphate metabolites (ATP, phosphocreatine, and inorganic phosphate), indicating specificity in the NAD{square} response. Exploratory analyses, dividing the blocks in two halves, suggested further reductions in NAD{square} and tNAD in the second halves of both stimulation blocks, though these trends were not statistically significant. Our findings demonstrate the feasibility of using fMRS at 7T to detect stimulus-induced dynamics in cerebral NAD{square} metabolism in vivo, providing insights into the interplay between glycolysis and oxidative phosphorylation during neural activation.

neuroscience↗

bioRxiv2024

High-fat and high-sucrose diet-induced hypothalamic inflammation shows sex specific features in mice

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-{gamma}, 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-, IL-6 and IL-13, but increased TGF-{beta}, while female mice showed over-expression of IFN-{gamma} 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.

molecular biology↗

bioRxiv2024

Microgliosis driven by palmitate exposure alters energy metabolism and extracellular vesicles release that impact behavior and systemic metabolism

Dietary patterns that include an excess of foods rich in saturated fat are associated with brain dysfunction. Although microgliosis has been proposed to play a key role in the development of brain dysfunction in diet-induced obesity (DIO), neuroinflammation with cytokine over-expression is often not always observed. Thus, mechanisms by which microglia contribute to brain impairment in DIO are uncertain. Using the BV2 cell model, we investigated the gliosis profile of microglia exposed to palmitate (200 {micro}mol/L), a saturated fatty acid abundant in high-fat diet and in the brain of obese individuals. We observed that microglia respond to a 24-hour palmitate exposure with increased proliferation, and with a metabolic network rearrangement that favors energy production from glycolysis rather than oxidative metabolism, despite stimulated mitochondria biogenesis. In addition, while palmitate did not induce increased cytokine expression, it modified the protein cargo of released extracellular vesicles (EVs). When administered intra-cerebroventricularly to mice, EVs from palmitate-exposed microglia in vitro led to memory impairment, depression-like behavior, and glucose intolerance, when compared to mice receiving EVs from vehicle-treated microglia. We conclude that microglia exposed to palmitate can mediate brain dysfunction through the cargo of shed EVs.

neuroscience↗

bioRxiv2023

Butyrate-producing bacteria as probiotic supplement: beneficial effects on metabolism and modulation of behavior in an obesity mouse model

Obesity is a risk factor for cardio-metabolic and neurological disease. The contribution of gut microbiota to derangements of the gut-brain axis in the context of obesity has been acknowledged, particularly through physiology modulation by short-chain fatty acids (SCFAs). Thus, probiotic interventions and administration of SCFAs have been employed with the purpose of alleviating symptoms in both metabolic and neurological disease. We have tested the effects of four butyrate-producing bacteria from the Lachnospiraceae family on the development of metabolic syndrome and behavioural alterations in a mouse model of diet-induced obesity. Male mice were fed either a high-fat diet (HFD) or an ingredient-matched control diet for 2 months, and bacteria cultures or culture medium were given by gavage to HFD-fed mice every second day. Assessment of the mice through a battery of metabolic and behaviour tests revealed that one of the administered bacteria affords some degree of protection against the development of obesity and its complications.

physiology↗

bioRxiv2022

Taurine or N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice

Obesity impacts brain metabolism and function, and constitutes a risk factor for dementia development. Long-term exposure to obesogenic diets leads to taurine accumulation in the hippocampus of rodents. Taurine has putative beneficial effects on cell homeostasis, and is reported to improve cognition. Therefore, hippocampal taurine accumulation in obese and diabetic models might constitute a counteracting response to metabolic stress. This study tested the hypothesis that treatment with taurine or with N-acetylcysteine (NAC), which provides cysteine for the synthesis of taurine and the antioxidant glutathione, prevent obesity-associated hippocampal alterations and memory impairment. Female mice were fed either a regular diet or a high-fat diet (HFD). For the same period, some mice had access to 3%(w/v) taurine or 3%(w/v) NAC in the drinking water. After 2 months, magnetic resonance spectroscopy was used to measure metabolite profiles. Then, memory was assessed in novel object and novel location recognition tests. HFD feeding caused memory impairment in both tests, and reduced concentration of lactate, phosphocreatine-to-creatine ratio, and the neuronal marker N-acetylaspartate in the hippocampus. Both taurine and NAC prevented HFD-induced memory impairment and N-acetylaspartate reduction. NAC, but not taurine, prevented the HFD-induced reduction of lactate and phosphocreatine-to-creatine ratio. Analysis of the metabolite profile further revealed prominent NAC/taurine-induced increase of glutamate and GABA levels in the hippocampus. We conclude that NAC and taurine prevent of neuronal dysfunction, while only NAC prevents energy metabolism dysregulation in HFD-induced obesity in female mice.

neuroscience↗

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↗