Abstract
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 low-grade 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.
Highlights
adipose tissue (AT) dysfunction plays a key role and is at the core of insulin resistance (IR) development [1]
We studied the immunometabolic characteristics in the symptom-free female volunteers and compared the relation and trends of the high vs. low adiponectin/leptin ratio (ALR) with their F/P insulin-glucose axis, lipidlipoprotein metabolism, and systemic inflammatory markers
They were chosen for deep phenotyping because their clinical characteristics show similar metabolic patterns that accurately represent the full database of 80 women
Summary
AT dysfunction plays a key role and is at the core of IR development [1]. IR is a chronic systemic inflammatory syndrome primarily triggered by macrophage infiltration into adipose tissue [2]. Interactions between macrophages and adipocytes [3] are the early molecular factors influencing AT dysfunction, resulting in local altered adipose tissue metabolism that progresses to altered systemic metabolism (mainly high leptin and low adiponectin circulating levels) and chronic lowgrade inflammation, leading to IR [4]. The recently developed adiponectin/leptin ratio (ALR) correlates with IR better than adiponectin or leptin alone It is strongly associated with surrogate measures of IR: the homoeostatic model assessment (HOMA) and the hyperinsulinemic-euglycemic clamp [7]. This emerging index decreases with increasing number of cardiometabolic risk factors reflecting the functionality of adipose tissue and negatively correlates with markers of low-grade chronic subclinical inflammation. A low (L)ALR as a marker of adipose tissue (AT) dysfunction is characterized by a lower secretion of adiponectin in relation to leptin levels, unhealthy adipose tissue hypoxia, proinflammatory macrophage polarization, altered adipokine profile and IR [9]
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