bims-ecmrat 2023-10-01 papers

Int J Mol Sci. 2023 Sep 14. pii: 14101. [Epub ahead of print]24(18):

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour.

Brooke L Farrugia, James Melrose.

This review examines the roles of HS-proteoglycans (HS-PGs) in general, and, in particular, perlecan and syndecan as representative examples and their interactive ligands, which regulate physiological processes and cellular behavior in health and disease. HS-PGs are essential for the functional properties of tissues both in development and in the extracellular matrix (ECM) remodeling that occurs in response to trauma or disease. HS-PGs interact with a biodiverse range of chemokines, chemokine receptors, protease inhibitors, and growth factors in immune regulation, inflammation, ECM stabilization, and tissue protection. Some cell regulatory proteoglycan receptors are dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic stabilization, plasticity, and specificity of interaction, promoting neurotransduction, neurogenesis, and differentiation. Ternary complexes of glypican-1 and Robbo-Slit neuroregulatory proteins direct axonogenesis and neural network formation. Specific neurexin-neuroligin complexes stabilize synaptic interactions and neural activity. Disruption in these interactions leads to neurological deficits in disorders of functional cognitive decline. Interactions with HS-PGs also promote or inhibit tumor development. Thus, HS-PGs have complex and diverse regulatory roles in the physiological processes that regulate cellular behavior and the functional properties of normal and pathological tissues. Specialized HS-PGs, such as the neurexins, pikachurin, and Eyes-shut, provide synaptic stabilization and specificity of neural transduction and also stabilize the axenome primary cilium of phototoreceptors and ribbon synapse interactions with bipolar neurons of retinal neural networks, which are essential in ocular vision. Pikachurin and Eyes-Shut interactions with an α-dystroglycan stabilize the photoreceptor synapse. Novel regulatory roles for HS-PGs controlling cell behavior and tissue function are expected to continue to be uncovered in this fascinating class of proteoglycan.

Keywords: ECM remodeling; HS; cellular proliferation and differentiation; cellular regulation; matrix stabilization; neural plasticity; neurogenesis; neurotransduction; phototransduction; regulation of angiogenesis; tissue development; tissue homeostasis; tissue protection

DOI: https://doi.org/10.3390/ijms241814101

Science. 2023 Sep 29. 381(6665): eabl7398

Integrative neurocircuits that control metabolism and food intake.

Jens C Brüning, Henning Fenselau.

Systemic metabolism has to be constantly adjusted to the variance of food intake and even be prepared for anticipated changes in nutrient availability. Therefore, the brain integrates multiple homeostatic signals with numerous cues that predict future deviations in energy supply. Recently, our understanding of the neural pathways underlying these regulatory principles-as well as their convergence in the hypothalamus as the key coordinator of food intake, energy expenditure, and glucose metabolism-have been revealed. These advances have changed our view of brain-dependent control of metabolic physiology. In this Review, we discuss new concepts about how alterations in these pathways contribute to the development of prevalent metabolic diseases such as obesity and type 2 diabetes mellitus and how this emerging knowledge may provide new targets for their treatment.

DOI: https://doi.org/10.1126/science.abl7398

J Endocrinol. 2023 Sep 01. pii: JOE-23-0180. [Epub ahead of print]

Adipose tissue fibrosis: the unwanted houseguest invited by obesity.

Christy M Gliniak, Line Pedersen, Philipp E Scherer.

The prevalence of obesity is increasing exponentially across the globe. The lack of effective treatment options for long-term weight loss has magnified the enormity of this problem. Studies continue to demonstrate that adipose tissue holds a biological memory that is one of the most important determinant of long-term weight homeostasis. This phenomenon is consistent with the metabolically dynamic role of adipose tissue: it adapts and expands to store for excess energy and serves as an endocrine organ capable of synthesizing a number of biologically active molecules that regulate metabolic homeostasis. An important component of the plasticity of adipose tissue is the extracellular matrix, essential for structural support, mechanical stability, cell signaling and function. Chronic obesity upends a delicate balance of extracellular matrix synthesis and degradation, and the ECM accumulates in such a way that prevents the plasticity and function of the diverse cell types in adipose tissue. A series of maladaptive responses among the cells in adipose tissue lead to inflammation and fibrosis, major mechanisms that explain the link between obesity and insulin resistance, risk of type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Adipose tissue fibrosis persists after weight loss and further enhances adipose tissue dysfunction if weight is regained. Here, we highlight the current knowledge of the cellular events governing adipose tissue ECM remodeling during development of obesity. Our goal is to delineate the relationship more clearly between adipose tissue ECM and metabolic disease, an important step towards better defining the pathophysiology of dysfunctional adipose tissue.

DOI: https://doi.org/10.1530/JOE-23-0180

Am J Physiol Cell Physiol. 2023 Sep 25.

Extracellular matrix contribution to disease progression and dysfunction in myopathy.

Ashlee M Long, GaHyun Lee, Alexis Demonbreun, Elizabeth M McNally.

Myopathic processes affect skeletal muscle and heart. In the muscular dystrophies, which are a subset of myopathies, muscle cells are gradually replaced by fibrosis and fat, impairing muscle function as well as regeneration and repair. In addition to skeletal muscle, these genetic disorders often also affect the heart, where fibrofatty infiltration progressively accumulates in the myocardium, impairing heart function. While considerable effort has focused on gene-corrective and gene-replacement approaches to stabilize myofibers and cardiomyocytes, the continual and ongoing deposition of extracellular matrix itself contributes to tissue and organ dysfunction. Transcriptomic and proteomic profiling, along with high resolution imaging and biophysical measurements, have been applied to define extracellular matrix components and their role in contributing to cardiac and skeletal muscle weakness. More recently, decellularization methods have been adapted to an on-slide format to preserve the spatial geography of the extracellular matrix, allowing new insight into matrix remodeling and its direct role in suppressing regeneration in muscle. This review highlights recent literature with focus on the extracellular matrix and molecular mechanisms that contribute to muscle and heart fibrotic disorders. We will also compare how the myopathic matrix differs from healthy matrix, emphasizing how the pathological matrix contributes to disease.

Keywords: Extracellular matrix; decellularization; fibrosi; heart; muscle

DOI: https://doi.org/10.1152/ajpcell.00182.2023

Metabolites. 2023 Aug 29. pii: 979. [Epub ahead of print]13(9):

The Role of Organokines in Obesity and Type 2 Diabetes and Their Functions as Molecular Transducers of Nutrition and Exercise.

Ji Ye Lim, Eunju Kim.

Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.

Keywords: adipokines; exercise; hepatokines; metabolic disease; myokines; nutrition; obesity; type 2 diabetes

DOI: https://doi.org/10.3390/metabo13090979

Nat Rev Endocrinol. 2023 Sep 25.

The evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.

Ibrahim AlZaim, Laura P M H de Rooij, Bilal N Sheikh, Emma Börgeson, Joanna Kalucka.

Adipose tissue is an endocrine organ and a crucial regulator of energy storage and systemic metabolic homeostasis. Additionally, adipose tissue is a pivotal regulator of cardiovascular health and disease, mediated in part by the endocrine and paracrine secretion of several bioactive products, such as adipokines. Adipose vasculature has an instrumental role in the modulation of adipose tissue expansion, homeostasis and metabolism. The role of the adipose vasculature has been extensively explored in the context of obesity, which is recognized as a global health problem. Obesity-induced accumulation of fat, in combination with vascular rarefaction, promotes adipocyte dysfunction and induces oxidative stress, hypoxia and inflammation. It is now recognized that obesity-associated endothelial dysfunction often precedes the development of cardiovascular diseases. Investigations have revealed heterogeneity within the vascular niche and dynamic reciprocity between vascular and adipose cells, which can become dysregulated in obesity. Here we provide a comprehensive overview of the evolving functions of the vasculature in regulating adipose tissue biology in health and obesity.

DOI: https://doi.org/10.1038/s41574-023-00893-6