Understanding the role of adipose tissue microenvironment in obesity-induced inflammation and insulin resistance

Abstract

Chronic obesity presents a formidable challenge to biomedical researchers as its association with metabolic disorders, notably insulin resistance (IR) and type 2 diabetes (T2D). In this study, we unravel a multifaceted interplay within the obese visceral white adipose tissue (vWAT) that drives adipocyte dysfunction, inflammation, and insulin resistance, offering potential therapeutic avenues for managing these conditions. During chronic obesity, the vWAT undergoes significant expansion generating a microenvironment (ATenv), characterized by elevated free fatty acids (FFAs) and hypoxia, triggering a cascade of pathogenic events. Here in this thesis, we revealed microenvironment significantly upregulates the expression of miR-210-3p in adipose tissue macrophages (ATMs), promoting the polarization of proinflammatory ATMs and the release of proinflammatory cytokines. Notably, the delivery of miR-210-3p mimic exacerbates macrophage inflammation even in the absence of lipid surge (HL co-stimulation), while miR-210-3p inhibition mitigates HL-induced inflammation. Mechanistically, miR-210-3p targets SOCS1, a negative regulator of the NF-κB p65 subunit which negatively influences the inflammatory pathway. The direct delivery of anti-miR-210-3p LNA in the vWAT rescues mice from obesity-induced adipose tissue inflammation, highlighting miR-210-3p inhibition in ATMs as a promising therapeutic strategy. Furthermore, obese ATenv orchestrates the release of miR-210-3p-enriched extracellular vesicles (EVs) from ATMs, which subsequently impair glucose metabolism in lean mice by targeting GLUT4 expression and disrupting the insulin signaling pathway. The therapeutic intervention using miR-210-3p inhibitor-LNA in vWAT rescues high-fat diet (HFD)-fed mice from obesity-induced systemic insulin resistance and glucose intolerance. Thus, targeting obese ATM-specific miR-210-3p holds promise as a therapeutic strategy for managing IR and T2D. In the context of obesity, a tremendous increase in adipocyte senescence is observed as adipocytes undergo irreversible growth arrest associated with the secretion of various adipokines, cytokines, chemokines, and extracellular matrix proteins that contribute to IR and T2D. Here we reveal that fetuin-A, previously recognized as a hepatokine and adipokine, serves as a nuclear regulatory protein in adipocytes under obese ATenv conditions. HIF-1α directly interacts with fetuin-A and mediates the nuclear migration, and activates senescence-associated secretory phenotypes (SASPs) leading to adipocyte senescence. Ectopic expression of HIF-1α and fetuin-A in adipocytes independently induces senescence, even in the absence of pathophysiological stimuli. Additionally, fetuin-A ablation rescues adipocytes from SASP activation and premature senescence in diet-induced obese mice. These findings shed light on a novel mechanism of adipocyte pathogenesis, underscoring the importance of nuclear fetuin-A and HIF-1α interaction in driving adipocyte senescence under obese ATenv conditions. Collectively, our study provides a comprehensive understanding of the multifaceted mechanisms underlying obesity-induced adipose tissue dysfunction and insulin resistance, offering potential therapeutic targets for addressing these critical health challenges.