Adipose tissue depot‐specific intracellular and extracellular cues contributing to insulin resistance in obese individuals

Abstract

Adipose tissue dysregulation in obesity strongly influences systemic metabolic homeostasis and is often linked to insulin resistance (IR). However, the molecular mechanisms underlying adipose tissue dysfunction in obesity are not fully understood. Herein, a proteomic analysis of subcutaneous (SC) and omental (OM) fat from lean subjects and obese individuals with different degrees of insulin sensitivity was performed to identify adipose tissue biomarkers related to obesity‐associated metabolic disease. Our results suggest that dysregulation of both adipose tissue extracellular matrix (ECM) organization and intracellular trafficking processes may be associated with IR in obesity. Thus, abnormal accumulation of the small leucine‐rich proteoglycan, lumican, as observed in SC fat of IR obese individuals, modifies collagen I organization, impairs adipogenesis and activates stress processes [endoplasmic reticulum and oxidative stress] in adipocytes. In OM fat, IR is associated with increased levels of the negative regulator of the Rab family of small GTPases, GDI2, which alters lipid storage in adipocytes by inhibiting insulin‐stimulated binding of the Rab protein, Rab18, to lipid droplets. Together, these results indicate that lumican and GDI2 might play depot‐dependent, pathogenic roles in obesity‐associated IR. Our findings provide novel insights into the differential maladaptive responses of SC and OM adipose tissue linking obesity to IR.

Adipose Tissue Macrophage Polarization in Healthy and Unhealthy Obesity

“…Adipocytes are surrounded by a network of ECM proteins that serve as a mechanical support and respond to different signaling events ( 60 ). AT expansion relies on adaptive cellular and extracellular responses to prevent ectopic lipid deposition and lipotoxicity ( 61 – 63 ). Within AT, collagens produced primarily by adipocytes and endothelial cells comprise most non-cell tissue mass, whereas integrins are the major tissue receptors for cell adhesion to ECM proteins ( 64 , 65 ).…”

Bioactive potential of natural biomaterials: identification, retention and assessment of biological properties

“…We characterise the significant biological motifs, structure, and complex architectures of common starting materials that dictate cell behaviour and tissue responses differentiating from disease phenotypes. 18 Cells are sensitive to organisational motifs discussed above, such as fibril status, 19 molecule length, and molecular weight 20 as these may indicate tissue degradation and induce an inflammatory response. Finally, this review aims to highlight the importance of target tissue and substrate material characterisation, starting material selection and processing based on innate biologically active motifs, with final validation of retained biological motifs in the final product to regenerate the target tissue.…”

Aquaporin-11 Contributes to TGF-β1-induced Endoplasmic Reticulum Stress in Human Visceral Adipocytes: Role in Obesity-Associated Inflammation

“…Growing evidence supports that obesity-associated inflammation and ER stress take also place in the subcutaneous fat depot [ 37 ]. In the context of obesity-associated insulin resistance, subcutaneous adipose tissue can be as deleterious as visceral fat, exhibiting increased markers of inflammation, oxidative, and ER stress [ 25 ]. Accordingly, our data showed that transcript and protein levels of AQP11 were higher in the subcutaneous adipose tissue of obese patients with type 2 diabetes than those found in individuals with normoglycemia.…”

“…Lipid droplets (LDs), cytosolic, and crude membrane fractions were isolated by centrifugation of protein extracts from differentiated adipocytes in sucrose density gradients according to our previously validated protocols [ 25 , 26 ]. Briefly, cells were rinsed with Ca 2+ - and Mg 2+ -free PBS (Invitrogen) and resuspended in 3 mL lysis buffer containing 25 mmol/L Tris-HCl, 100 mmol/L KCl, 1 mmol/L EDTA, 5 mmol/L EGTA, and 1 µg/mL anti-protease cocktail (pH 7.40).…”