Preterm birth: A neuroinflammatory origin for metabolic diseases?

Preterm birth and its related complications have become more and more common as neonatal medicine advances. The concept of "developmental origins of health and disease" has raised awareness of adverse perinatal events in the development of diseases later in life. To explore this concept, we propose that encephalopathy of prematurity (EoP) as a potential pro-inflammatory early life event becomes a novel risk factor for metabolic diseases in children/adolescents and adulthood.

Dietary fatty acid composition drives neuroinflammation and impaired behavior in obesity.

Nutrient composition in obesogenic diets may influence the severity of disorders associated with obesity such as insulin-resistance and chronic inflammation. Here we hypothesized that obesogenic diets rich in fat and varying in fatty acid composition, particularly in omega 6 (ω6) to omega 3 (ω3) ratio, have various effects on energy metabolism, neuroinflammation and behavior. Mice were fed either a control diet or a high fat diet (HFD) containing either low (LO), medium (ME) or high (HI) ω6/ω3 ratio.

Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation.

Microglia are crucial for brain homeostasis, and dysfunction of these cells is a key driver in most neurodegenerative diseases, including peroxisomal leukodystrophies. In X-linked adrenoleukodystrophy (X-ALD), a neuroinflammatory disorder, very long-chain fatty acid (VLCFA) accumulation due to impaired degradation within peroxisomes results in microglial defects, but the underlying mechanisms remain unclear. Using CRISPR/Cas9 gene editing of key genes in peroxisomal VLCFA breakdown (, and ), we recently established easily accessible microglial BV-2 cell models to study the impact of dysfunctional peroxisomal β-oxidation and revealed a disease-associated microglial-like signature in these cell lines.

Peroxisomal defects in microglial cells induce a disease-associated microglial signature.

Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process.

Interactions between the regulatory peptide 26RFa (QRFP) and insulin in the regulation of glucose homeostasis in two complementary models: The high fat 26RFa-deficient mice and the streptozotocin insulin-deficient mice.

The regulatory peptide 26RFa (QRFP) is involved in the control of glucose homeostasis at the periphery by acting as an incretin, and in the brain by mediating the central antihyperglycemic effect of insulin, indicating the occurrence of a close relationship between 26RFa and insulin in the regulation of glucose metabolism. Here, we investigated the physiological interactions between 26RFa and insulin in two complementary models i.e.

Two Argan Oil Phytosterols, Schottenol and Spinasterol, Attenuate Oxidative Stress and Restore LPS-Dysregulated Peroxisomal Functions in and Wild-Type BV-2 Microglial Cells.

Oxidative stress and inflammation are the key players in neuroinflammation, in which microglia dysfunction plays a central role. Previous studies suggest that argan oil attenuates oxidative stress, inflammation, and peroxisome dysfunction in mouse brains. In this study, we explored the effects of two major argan oil (AO) phytosterols, Schottenol (Schot) and Spinasterol (Spina), on oxidative stress, inflammation, and peroxisomal dysfunction in two murine microglial BV-2 cell lines, () and ()-deficient cells challenged with LPS treatment.

Normal and Pathological NRF2 Signalling in the Central Nervous System.

The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases.

Microgliosis: a double-edged sword in the control of food intake.

Maintaining energy balance is essential for survival and health. This physiological function is controlled by the brain, which adapts food intake to energy needs. Indeed, the brain constantly receives a multitude of biological signals that are derived from digested foods or that originate from the gastrointestinal tract, energy stores (liver and adipose tissues) and other metabolically active organs (muscles).

The 26RFa (QRFP)/GPR103 neuropeptidergic system in mice relays insulin signalling into the brain to regulate glucose homeostasis.

Aims/hypothesis: 26RFa (pyroglutamilated RFamide peptide [QRFP]) is a biologically active peptide that regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity at the periphery. 26RFa is also produced by a neuronal population localised in the hypothalamus. In this study we investigated whether 26RFa neurons are involved in the hypothalamic regulation of glucose homeostasis.

The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.

Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated.

Evidence for Constitutive Microbiota-Dependent Short-Term Control of Food Intake in Mice: Is There a Link with Inflammation, Oxidative Stress, Endotoxemia, and GLP-1?

Although prebiotics, probiotics, and fecal transplantation can alter the sensation of hunger and/or feeding behavior, the role of the constitutive gut microbiota in the short-term regulation of food intake during normal physiology is still unclear. An antibiotic-induced microbiota depletion study was designed to compare feeding behavior in conventional and microbiota-depleted mice. Tissues were sampled to characterize the time profile of microbiota-derived signals in mice during consumption of either standard or high-fat food for 1 h.

Acute but Not Chronic Central Administration of the Neuropeptide 26RFa (QRFP) Improves Glucose Homeostasis in Obese/Diabetic Mice.

Introduction: The aim of the study is to investigate whether acute or chronic central administration of the hypothalamic neuropeptide 26RFa may ameliorate the glycemic control of obese/diabetic mice.

Methods: Mice were treated for 4 months with a high-fat (HF) diet and received a single i.c.

Dietary switch to Western diet induces hypothalamic adaptation associated with gut microbiota dysbiosis in rats.

Background: Early hyperphagia and hypothalamic inflammation encountered after Western diet (WD) are linked to rodent propensity to obesity. Inflammation in several brain structures has been associated with gut dysbiosis. Since gut microbiota is highly sensitive to dietary changes, we hypothesised that immediate gut microbiota adaptation to WD in rats is involved in inflammation-related hypothalamic modifications.

Dietary fat exacerbates postprandial hypothalamic inflammation involving glial fibrillary acidic protein-positive cells and microglia in male mice.

In humans, obesity is associated with brain inflammation, glial reactivity, and immune cells infiltration. Studies in rodents have shown that glial reactivity occurs within 24 hr of high-fat diet (HFD) consumption, long before obesity development, and takes place mainly in the hypothalamus (HT), a crucial brain structure for controlling body weight. Here, we sought to characterize the postprandial HT inflammatory response to 1, 3, and 6 hr of exposure to either a standard diet (SD) or HFD.

Postprandial Hyperglycemia Stimulates Neuroglial Plasticity in Hypothalamic POMC Neurons after a Balanced Meal.

Mechanistic studies in rodents evidenced synaptic remodeling in neuronal circuits that control food intake. However, the physiological relevance of this process is not well defined. Here, we show that the firing activity of anorexigenic POMC neurons located in the hypothalamus is increased after a standard meal.

Glucose homeostasis is impaired in mice deficient in the neuropeptide 26RFa (QRFP).

Introduction: 26RFa (pyroglutamyl RFamide peptide (QRFP)) is a biologically active peptide that has been found to control feeding behavior by stimulating food intake, and to regulate glucose homeostasis by acting as an incretin. The aim of the present study was thus to investigate the impact of 26RFa gene knockout on the regulation of energy and glucose metabolism.

Research Design And Methods: 26RFa mutant mice were generated by homologous recombination, in which the entire coding region of prepro26RFa was replaced by the iCre sequence.

Centrifugal projections to the main olfactory bulb revealed by transsynaptic retrograde tracing in mice.

A wide range of evidence indicates that olfactory perception is strongly involved in food intake. However, the polysynaptic circuitry linking the brain areas involved in feeding behavior to the olfactory regions is not well known. The aim of this article was to examine such circuits.

The neuropeptide 26RFa in the human gut and pancreas: potential involvement in glucose homeostasis.

Objective: Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia.

Lack of Hypothalamus Polysialylation Inducibility Correlates With Maladaptive Eating Behaviors and Predisposition to Obesity.

High variability exists in individual susceptibility to develop overweight in an obesogenic environment and the biological underpinnings of this heterogeneity are poorly understood. In this brief report, we show in mice that the vulnerability to diet-induced obesity is associated with low level of polysialic acid-neural cell adhesion molecule (PSA-NCAM), a factor of neural plasticity, in the hypothalamus. As we previously shown that reduction of hypothalamic PSA-NCAM is sufficient to alter energy homeostasis and promote fat storage under hypercaloric pressure, inter-individual variability in hypothalamic PSA-NCAM might account for the vulnerability to diet-induced obesity.

Brain Control of Plasma Cholesterol Involves Polysialic Acid Molecules in the Hypothalamus.

The polysialic acid (PSA) is a large glycan that is added to cell-surface proteins during their post-translational maturation. In the brain, PSA modulates distances between cells and controls the plasticity of the nervous system. In the hypothalamus, PSA is involved in many aspects of energy balance including food intake, osmoregulation, circadian rhythm, and sleep.

Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis.

The mediobasal hypothalamus (MBH) contains neurons capable of directly detecting metabolic signals such as glucose to control energy homeostasis. Among them, glucose-excited (GE) neurons increase their electrical activity when glucose rises. In view of previous work, we hypothesized that transient receptor potential canonical type 3 (TRPC3) channels are involved in hypothalamic glucose detection and the control of energy homeostasis.

Plasticity of the Melanocortin System: Determinants and Possible Consequences on Food Intake.

The melanocortin system is one of the most important neuronal pathways involved in the regulation of food intake and is probably the best characterized. Agouti-related peptide (AgRP) and proopiomelanocortin (POMC) expressing neurons located in the arcuate nucleus of the hypothalamus are the key elements of this system. These two neuronal populations are sensitive to circulating molecules and receive many excitatory and inhibitory inputs from various brain areas.

The histone acetyltransferase MOF activates hypothalamic polysialylation to prevent diet-induced obesity in mice.

Overfeeding causes rapid synaptic remodeling in hypothalamus feeding circuits. Polysialylation of cell surface molecules is a key step in this neuronal rewiring and allows normalization of food intake. Here we examined the role of hypothalamic polysialylation in the long-term maintenance of body weight, and deciphered the molecular sequence underlying its nutritional regulation.