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 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.

Keywords: Adipose tissue dysfunction; immunometabolism; non-coding microRNAs; postprandial tissue biopsies; shotgun lipidomics.

Figure 1.

Mean ALR in our symptom-free female participants

Figure 2.

Mean leptin, adiponectin, Adiponectin/Leptin ratio and anthropometric phenotypes of participants in the GEMM study (ALR and Age with a P-value ≤ 0.05)

Figure 3.

Immunometabolic and proinflammatory profile of participants in the GEMM study (non-significant P-values)

Figure 4.

Immunometabolic, insulin resistance, liver enzyme profile, postprandial insulin-glucose axis and triglyceride curves of female participants in the GEMM study (n = 14). Adipo-IR Index, HOMA-IR, ALT/GPT and AST/GOT with a P-value ≤ 0.05. Area under the curve (AUC) for glucose in the (h) ALR group and (l) ALG (13,743 and 13,144, 5% difference [diff.]). AUC for insulin and GLP-1 in the (H) ALR group (5055 and 15,143) compared to the (L) ALG (9362 and 19,327) respectively, showed an 85% and 28% diff

Figure 5.

Direct measurements performed for fasting (0ʹ) and fed (180ʹ) subcutaneous fat transcriptomic profiling looking for molecular trends in adipose tissue dysfunction or inflammation differential gene expression in key proinflammatory and anti-inflammatory genes. The expression of the anti-inflammatory gene ANG was significantly decreased in the (l)ALR subgroup in fasting