Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation.

Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission.

Interferon γ: a master cytokine in microglia-mediated neural network dysfunction and neurodegeneration.

Traditionally, lymphocytic interferon γ (IFN-γ) was considered to be a simple 'booster' of proinflammatory responses by microglia (brain-resident macrophages) during bacterial or viral infection. Recent slice culture (in situ) and in vivo studies suggest, however, that IFN-γ has a unique role in microglial activation. Priming by IFN-γ results in proliferation (microgliosis), enhanced synapse elimination, and moderate nitric oxide release sufficient to impair synaptic transmission, gamma rhythm activity, and cognitive functions.

Priming of microglia by type II interferon is lasting and resistant to modulation by interleukin-10 in situ.

Immunological priming by type II interferon (IFN-γ) is crucial for evoking neurotoxic phenotypes of microglia (tissue-resident macrophages). We report that serial exposure of hippocampal slice cultures to IFN-γ and lipopolysaccharide (Toll-like receptor 4 ligand) induces high release of IL-6, TNF-α and nitric oxide, concomitant loss of electrical network activity (neuronal gamma oscillations) and neurodegeneration. Notably, these effects are still present after 3 days of IFN-γ removal but neither mimicked by IFN-α nor attenuated by anti-inflammatory cytokine, IL-10.

TLR2- and TLR3-activated microglia induce different levels of neuronal network dysfunction in a context-dependent manner.

Recognition of pathogen- or damage-associated molecular patterns (PAMPs, DAMPs) by innate Toll-like receptors (TLRs) is central to the activation of microglia (brain macrophages) in many CNS diseases. Notably, TLR-mediated microglial activation is complex and modulated by additional exogenous and endogenous immunological signals. The impact of different microglial reactive phenotypes on electrical activity and neurotransmission is widely unknown, however.

Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity.

Objective: The systemic function of CETP has been well characterized. CETP plasma activity reduces HDL cholesterol and thus increases the risk of atherosclerosis. Here, we investigated whether CETP expression modulate adiposity.

Microglia and lipids: how metabolism controls brain innate immunity.

Microglia are universal sensors of alterations in CNS physiology. These cells integrate complex molecular signals and undergo comprehensive phenotypical remodeling to adapt inflammatory responses. In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease.

GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ.

Background: The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30-70 Hz).

Neuronal gamma oscillations and activity-dependent potassium transients remain regular after depletion of microglia in postnatal cortex tissue.

Microglial cells (resident macrophages) feature rapid activation in CNS disease and can acquire multiple phenotypes exerting neuroprotection or neurotoxicity. The functional impact of surveying ("resting") microglia on neural excitability and neurotransmission in physiology is widely unknown, however. We addressed this issue in male rat hippocampal slice cultures (in situ) by pharmacological microglial ablation within days and by characterizing neuronal gamma-band oscillations (30-70 Hz) that are highly sensitive to neuromodulators and disturbances in ion and energy regulation.

Selective inhibition of mitochondrial respiratory complexes controls the transition of microglia into a neurotoxic phenotype in situ.

Microglia are tissue resident macrophages (innate immunity) and universal sensors of alterations in CNS physiology. In response to pathogen or damage signals, microglia feature rapid activation and can acquire different phenotypes exerting neuroprotection or neurotoxicity. Although transcriptional aspects of microglial phenotypic transitions have been described, the underlying metabolic reprogramming is widely unknown.

Distinct metabolic patterns during microglial remodeling by oleate and palmitate.

Microglial activation by oleate and palmitate differentially modulates brain inflammatory status. However, the metabolic reprogramming supporting these reactive phenotypes remains unknown. Employing real-time metabolic measurements and lipidomic analysis, we show that both fatty acids promote microglial oxidative metabolism, while lipopolysaccharide (LPS) enhances glycolytic rates.

Priming of microglia with IFN-γ slows neuronal gamma oscillations in situ.

Type II IFN (IFN-γ) is a proinflammatory T lymphocyte cytokine that serves in priming of microglia-resident CNS macrophages-during the complex microglial activation process under pathological conditions. Priming generally permits an exaggerated microglial response to a secondary inflammatory stimulus. The impact of primed microglia on physiological neuronal function in intact cortical tissue (in situ) is widely unknown, however.

Resilient hepatic mitochondrial function and lack of iNOS dependence in diet-induced insulin resistance.

Obesity-derived inflammation and metabolic dysfunction has been related to the activity of the inducible nitric oxide synthase (iNOS). To understand the interrelation between metabolism, obesity and NO., we evaluated the effects of obesity-induced NO.

Cell culture models of fatty acid overload: Problems and solutions.

High plasma levels of fatty acids occur in a variety of metabolic diseases. Cellular effects of fatty acid overload resulting in negative cellular responses (lipotoxicity) are often studied in vitro, in an attempt to understand mechanisms involved in these diseases. Fatty acids are poorly soluble, and thus usually studied when complexed to albumins such as bovine serum albumin (BSA).

Hypothalamic mitochondrial abnormalities occur downstream of inflammation in diet-induced obesity.

Hypothalamic dysfunction is a common feature of experimental obesity. Studies have identified at least three mechanisms involved in the development of hypothalamic neuronal defects in diet-induced obesity: i, inflammation; ii, endoplasmic reticulum stress; and iii, mitochondrial abnormalities. However, which of these mechanisms is activated earliest in response to the consumption of large portions of dietary fats is currently unknown.

Caloric restriction increases brain mitochondrial calcium retention capacity and protects against excitotoxicity.

Caloric restriction (CR) protects against many cerebral pathological conditions that are associated with excitotoxic damage and calcium overload, although the mechanisms are still poorly understood. Here we show that CR strongly protects against excitotoxic insults in vitro and in vivo in a manner associated with significant changes in mitochondrial function. CR increases electron transport chain activity, enhances antioxidant defenses, and favors mitochondrial calcium retention capacity in the brain.

Diluted serum from calorie-restricted animals promotes mitochondrial β-cell adaptations and protect against glucolipotoxicity.

β-cells quickly adjust insulin secretion to oscillations in nutrients carried by the blood, acting as fuel sensors. However, most studies of β-cell responses to nutrients do not discriminate between fuel levels and signaling components present in the circulation. Here we studied the effect of serum from calorie-restricted rats versus serum from rats fed ad libitum, diluted tenfold in the medium, which did not contribute significantly to the pool of nutrients, on β-cell mitochondrial function and dynamics under regular and high-nutrient culture conditions.

Intermittent fasting results in tissue-specific changes in bioenergetics and redox state.

Intermittent fasting (IF) is a dietary intervention often used as an alternative to caloric restriction (CR) and characterized by 24 hour cycles alternating ad libitum feeding and fasting. Although the consequences of CR are well studied, the effects of IF on redox status are not. Here, we address the effects of IF on redox state markers in different tissues in order to uncover how changes in feeding frequency alter redox balance in rats.

Intermittent fasting induces hypothalamic modifications resulting in low feeding efficiency, low body mass and overeating.

Intermittent fasting (IF) is an often-used intervention to decrease body mass. In male Sprague-Dawley rats, 24 hour cycles of IF result in light caloric restriction, reduced body mass gain, and significant decreases in the efficiency of energy conversion. Here, we study the metabolic effects of IF in order to uncover mechanisms involved in this lower energy conversion efficiency.

Mitochondrial compartmentalization of redox processes.

Knowledge of location and intracellular subcompartmentalization is essential for the understanding of redox processes, because oxidants, owing to their reactive nature, must be generated close to the molecules modified in both signaling and damaging processes. Here we discuss known redox characteristics of various mitochondrial microenvironments. Points covered are the locations of mitochondrial oxidant generation, characteristics of antioxidant systems in various mitochondrial compartments, and diffusion characteristics of oxidants in mitochondria.

Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance.

Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings. We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity.