Izgilov, R. | bioRxiv Science

bioRxiv2026

SVEP1 couples adipose niche remodeling to macrophage activation and impaired metabolism in obesity

The extracellular matrix (ECM) of adipose tissue regulates metabolic homeostasis, yet how ECM composition drives adipose dysfunction in obesity remains only partially defined. Multi-omics profiling of visceral adipose tissue identified the multidomain ECM protein SVEP1 as a candidate regulator of adipose remodeling; SVEP1 was elevated in obese human adipose tissue and correlated with insulin resistance and systemic inflammation, and interaction analysis predicted associations with ECM proteins, integrins, and cytoskeletal regulators. On a chow diet, Svep1 heterozygous (Svep1+/-) mice gained less weight with lower fasting glucose, and their adipocytes showed enhanced lipolysis and AMPK activation. On a high-fat diet, Svep1+/- mice exhibited attenuated adiposity, improved glucose tolerance and insulin sensitivity, and fewer adipose macrophages with a shift away from a pro-inflammatory profile, alongside downregulation of inflammatory, lipid-metabolic, and ECM-remodeling pathways. Decellularized Svep1+/- matrix altered macrophage adhesion and phenotype relative to Svep1+/+ matrix, identifying SVEP1 as a matrix-borne mediator coupling adipose remodeling to immune activation and metabolic impairment. Together, these findings position the adipose ECM as an active driver of immunometabolic dysfunction and nominate SVEP1 and its receptor network as candidate targets in obesity.

cell biology↗

bioRxiv2023

Advance Glycation End-products induction accelerate amyloid deposits in adipocyte`s lipid droplets

Adipose tissue dysfunction is central to insulin resistance, and the emergence of type 2 diabetes (T2D) is associated with elevated levels of carbonyl metabolites from glucose metabolism. In this study, using methylglyoxal (MGO) and glycolaldehyde (GAD) carbonyl metabolites, induced protein glycation leading to misfolding and {beta}-sheet formation and generation of advanced glycation end products (AGEs). The formed AGEs compromise adipocytes activity. Microscopic and spectroscopic assays were used to examine the impact of MGO and GAD on lipid droplet - associated proteins. The results provide information about how glycation leads to the appearance of amyloidogenic proteins formation that hinders metabolism and autophagy in adipocytes. We measured the beneficial effects of metformin, an anti-diabetic drug, on misfolded protein as assessed by thioflavin (ThT) spectroscopy and improved autophagy. In vitro findings were complemented by in vivo analysis of white adipose tissue (WAT), where lipid droplet-associated {beta}-amyloid deposits were predominantly linked to adipose triglyceride lipase (ATGL), a lipid droplet protein. Bioinformatics, imaging, and biochemical methods affirm ATGLs role in {beta}-sheet secondary structure creation. Our results highlighted the pronounced presence of amyloidogenic proteins in adipocytes treated with carbonyl compounds, potentially reshaping our understanding of adipocyte pathology in the context of T2D. This in-depth exploration offers novel perspectives on related pathophysiology and underscores the potential of adipocytes as pivotal therapeutic targets, bridging T2D, amyloidosis, protein glycation, and adipocyte malfunction. Significance StatementThe generation of advanced glycation end products (AGEs) has a strong connection to diabetes severity . Adipose tissue is known to play a key role in the metabolic impairment and obesity associated with diabetes. We used the carbonyl compounds methylglyoxal (MGO) and glycolaldehyde (GAD) to create AGEs in adipocytes. The results of this study indicate that glycation not only affects cell metabolism and impairs adipocyte lipolysis, but also alters autophagy and increases protein amyloid deposits related to the membrane of lipid droplets. We identify the ATGL as a protein prone to {beta} sheet alteration. consequently, ATGL emerges as a pivotal actor in lipid droplet metabolism and a prospective therapeutic target for T2D complications.

cell biology↗