Search bioRxivSearch

bioRxiv · 10.1101/615674

Brown adipose tissue remodeling precedes cardiometabolic abnormalities independent of overweight in fructose-fed mice

Abstract

ObjectivesTo investigate the early cardiometabolic abnormalities along with WAT and BAT remodeling in short-term fructose feeding mice model.\n\nMethodsMice (n=10-11/group) were fed for four weeks with control diet (AIN93-M) or experimental diets rich in glucose or fructose. We investigated body weight, body adiposity, blood glucose, lipid and hepatic parameters, and white (WAT) and brown adipose tissue (BAT) histopathology.\n\nResultsFructose feeding promoted neither weight gain nor hypertrophy of visceral and subcutaneous WAT depots, but the fat was redistributed toward visceral depots. Glucose, lipid and hepatic metabolic dysfunction were not yet noticed in fructose-fed mice, with the exception for an elevation in total cholesterol and hepatic weight without steatosis. BAT mass did not increase, and it was proportionally reduced compared with visceral WAT in fructose feed mice. BAT suffered premature adverse morphological remodeling, characterized by increased lipid deposition per tissue area in enlarged intracellular lipid droplets.\n\nConclusionShort-term fructose feeding redistributes body fat, changes the proportion of BAT to visceral fat, and promotes BAT adverse remodeling, characterized by enlarged intracellular lipid droplets.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Queiroz Machado, T., Cristina Pereira-Silva, D., Ferreira Goncalves, L., Fernandes-Santos, C.. 2019-04-22. Brown adipose tissue remodeling precedes cardiometabolic abnormalities independent of overweight in fructose-fed mice. https://doi.org/10.1101/615674

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology

REVERSIBLE PULMONARY TRUNK BANDING. XI:MYOCARDIAL VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN YOUNG GOATS SUBMITTED TO VENTRICULAR RETRAINING

BackgroundVentricle retraining has been extensively studied by our laboratory. Previous studies have demonstrated that intermittent overload causes a more efficient ventricular hypertrophy. The adaptive mechanisms involved in the ventricle retraining are not completely established. This study assessed vascular endothelial growth factor (VEGF) expression in the ventricles of goats submitted to systolic overload.\n\nMethodsTwenty-one young goats were divided into 3 groups (7 animals each): control, 96-hour continuous systolic overload, and intermittent systolic overload (four 12-hour periods of systolic overload paired with 12-hour resting period). During the 96-hour protocol, systolic overload was adjusted to achieve a right ventricular (RV) / aortic pressure ratio of 0.7. Hemodynamic evaluations were performed daily before and after systolic overload. Echocardiograms were obtained preoperatively and at protocol end to measure cardiac masses thickness. At study end, the animals were killed for morphologic evaluation and immunohistochemical assessment of VEGF expression.\n\nResultsRV-trained groups developed hypertrophy of RV and septal masses, confirmed by increased weight and thickness, as expected. In the study groups, there was a small but significantly increased water content of the RV and septum compared with those in the control group (p<0.002). VEGF expression in the RV myocardium was greater in the intermittent group (2.89% {+/-} 0.41%) than in the continuous (1.80% {+/-} 0.19%) and control (1.43% {+/-} 0.18%) groups (p<0.023).\n\nConclusionsIntermittent systolic overload promotes greater upregulation of VEGF expression in the subpulmonary ventricle, an adaptation that provides a mechanism for increased myocardial perfusion during the rapid myocardial hypertrophy of young goats.

pathology

Nimodipine prevents the development of spasticity after spinal cord injury

Spasticity, one of the most frequent comorbidities of spinal cord injury (SCI), disrupts motor recovery and quality of life. Despite major progress in neurorehabilitative and pharmacological approaches, no curative treatment for spasticity exists. Here, we show in a mouse model of chronic SCI that treatment with nimodipine -- an FDA-approved L-type calcium channel blocker -- starting in the acute phase of SCI completely prevents the development of spasticity measured as increased muscle tone and spontaneous spasms. The aberrant muscle activities are permanently blocked even after termination of the treatment. Constitutive and conditional silencing in neuronal subtypes of CaV 1.3 channels shows that preventive effect of nimodipine on spasticity after SCI is mediated by the neuronal CaV 1.3 channels. This study identifies a potentially curative treatment protocol with a specific target for the prevention of spasticity after SCI.

pathology