Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice.

Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.

Methylglyoxal, a highly reactive dicarbonyl compound, as a threat for blood brain barrier integrity.

The brain is a highly metabolically active organ requiring a large amount of glucose. Methylglyoxal (MGO), a by-product of glucose metabolism, is known to be involved in microvascular dysfunction and is associated with reduced cognitive function. Maintenance of the blood-brain barrier (BBB) is essential to maintain optimal brain function and a large amount of evidence indicates negative effects of MGO on BBB integrity. In this review, we summarized the current literature on the effect of MGO on the different cell types forming the BBB. BBB damage by MGO most likely occurs in brain endothelial cells and mural cells, while astrocytes are most resistant to MGO. Microglia on the other hand appear to be not directly influenced by MGO but rather produce MGO upon activation. Although there is clear evidence that MGO affects components of the BBB, the impact of MGO on the BBB as a multicellular system warrants further investigation. Diminishing MGO stress can potentially form the basis for new treatment strategies for maintaining optimal brain function.

Constituent-based quasi-linear viscoelasticity: a revised quasi-linear modelling framework to capture nonlinear viscoelasticity in arteries.

Arteries exhibit fully nonlinear viscoelastic behaviours (i.e. both elastically and viscously nonlinear). While elastically nonlinear arterial models are well established, effective mathematical descriptions of nonlinear viscoelasticity are lacking. Quasi-linear viscoelasticity (QLV) offers a convenient way to mathematically describe viscoelasticity, but its viscous linearity assumption is unsuitable for whole-wall vascular applications. Conversely, application of fully nonlinear viscoelastic models, involving deformation-dependent viscous parameters, to experimental data is impractical and often reduces to identifying specific solutions for each tested loading condition. The present study aims to address this limitation: By applying QLV theory at the wall constituent rather than at the whole-wall level, the deformation-dependent relative contribution of the constituents allows to capture nonlinear viscoelasticity with a unique set of deformation-independent model parameters. Five murine common carotid arteries were subjected to a protocol of quasi-static and harmonic, pseudo-physiological biaxial loading conditions to characterise their viscoelastic behaviour. The arterial wall was modelled as a constrained mixture of an isotropic elastin matrix and four families of collagen fibres. Constituent-based QLV was implemented by assigning different relaxation functions to collagen- and elastin-borne parts of the wall stress. Nonlinearity in viscoelasticity was assessed via the pressure dependency of the dynamic-to-quasi-static stiffness ratio. The experimentally measured ratio increased with pressure, from 1.03 [Formula: see text] 0.03 (mean [Formula: see text] standard deviation) at 80-40 mmHg to 1.58 [Formula: see text] 0.22 at 160-120 mmHg. Constituent-based QLV captured well this trend by attributing the wall viscosity predominantly to collagen fibres, whose recruitment starts at physiological pressures. In conclusion, constituent-based QLV offers a practical and effective solution to model arterial viscoelasticity.

Achieving brain clearance and preventing neurodegenerative diseases-A glymphatic perspective.

Age-related neurodegenerative diseases are a growing burden to society, and many are sporadic, meaning that the environment, diet and lifestyle play significant roles. Cerebrospinal fluid (CSF)-mediated clearing of brain waste products via perivascular pathways, named the glymphatic system, is receiving increasing interest, as it offers unexplored perspectives on understanding neurodegenerative diseases. The glymphatic system is involved in clearance of metabolic by-products such as amyloid-ß from the brain, and its function is believed to lower the risk of developing some of the most common neurodegenerative diseases. Here, we present magnetic resonance imaging (MRI) data on the heart cycle's control of CSF flow in humans which corroborates findings from animal studies. We also review the importance of sleep, diet, vascular health for glymphatic clearance and find that these factors are also known players in brain longevity.