Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study

Abstract

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic lowgrade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Modeling Adipogenesis: Current and Future Perspective

“…The path to attain this goal is already being paved. Characterizing adipose tissue dysfunction by analyzing non-coding microRNAs and shotgun lipidomics profiles may be considered as a legitimate starting point [ 142 ]. Investigating the role of long noncoding RNAs in adipogenesis regulation may also direct the current research to the right track [ 143 ].…”

Working Hypothesis for Glucose Metabolism and SARS-CoV-2 Replication: Interplay Between the Hexosamine Pathway and Interferon RF5 Triggering Hyperinflammation. Role of BCG Vaccine?

“…The detrimental consequences are not hard to imagine when this life-threatening hyperinflammatory HBP-GlcNAc-OGT-IRF5-interferon-SARS-CoV-2 pathway from the COVID-19 pandemic meets with CLGSPI found in common, complex highly prevalent pandemics such as obesity and diabetes, also found in not so old individuals with symptom-free adipose tissue dysfunction, insulin resistance, the metabolic syndrome and/or prediabetes (13,47). These four groups of individuals present postprandial hyperglycemia which is one of the earliest abnormalities of glucose homeostasis associated with dysglycemic states (48).…”

“…These two subgroups are also at high-risk to develop the cytokine storm. They have in common a chronic systemic low-grade subclinical proinflammatory (CLGSPI) state (12) characterized by adipose tissue dysfunction (ATdys) (13) and macrophage polarization in adipose tissue, low adiponectin levels, cytokines and circulating inflammatory C-reactive protein (CRP) that perpetuates this deleterious CLGSPI and promotes insulin resistance (14). These subgroups of individuals with underlying but undetected postprandial dysglycemia, CLGSPI and ATdys present a proinflamatory pathology that is highly underestimated and rarely diagnosed among symptom-free individuals in the practice setting.…”

Dysfunctional Adiposity Index as a Useful Clinical Tool for Early Identification of Adipose Tissue Morpho-Functional Abnormalities and Cardiometabolic Disorders in Apparently Healthy Subjects

“…Adiponectin/leptin ratio was calculated as indicator of adipose tissue functionality. [22,30] The homeostatic model assessment of insulin resistance (HOMA-IR) index was calculated using the formula: HOMA-…”

“…The ALR has been proposed as an emerging biomarker of adipose tissue dysfunction that correlates with insulin resistance, metabolic abnormalities and in ammatory cytokines. [22,30] On the other hand, reduced adipocytes cell number along with enlarged size have been considered morphological indicators of hypertrophic adipocytes that play a role in obesity-related cardiovascular and metabolic abnormalities. [15][16][17] Data of the present study indicates that ALR signi cantly correlates with subcutaneous adipocytes number (r = 0.525; p = 0.001) and area (r = -0.431; p = 0.009), as well as with the relation of area/number of adipocytes (r = -0.529; p = 0.001) as indicator of morphologically abnormal adipocytes.…”