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Abstract Objective Although debated, metabolic health characterizes 10–25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. Methods Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases. Results and conclusions Our study showed that glucose intolerance and insulin resistance co-operate to remodel adipocyte transcriptome. We also identified the Nuclear Export Mediator Factor (NEMF) and the Ectoderm-Neural Cortex 1 (ENC1) as novel potential targets in the management of metabolic health in human obesity. Graphical abstract Image 1 Highlights • Healthy obese individuals maintain glucose tolerance and insulin sensitivity. • Glucose intolerance primarily remodels adipocyte transcriptome in human obesity. • Insulin resistance co-operates with glucose tolerance to remodel adipocyte transcriptome. • NEMF and ENC1 are potential targets to manage metabolic health in human obesity. [ABSTRACT FROM AUTHOR]

Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes). HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (N liver fat = 1054, N HIC = 2254; N alanineaminotranferase = 1985, N HIC = 2251). BMI-related SNPs were causally associated with HIC (N BMI = 2772, N HIC = 2259, p < 0.001) but not waist circumference-SNPs (N SNPs-waist circumference = 2751, N HIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (N insulin sensitivity = 2752, N HIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (N C-reactive protei n = 2660, N HIC = 2240; N HDL = 2694, N HIC = 2275). This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction. • Reduced hepatic insulin clearance could underlie peripheral hyperinsulinemia, an early manifestation of type 2 diabetes. • A potential inhibitor of hepatic insulin clearance could be hepatic steatosis which negatively associates with clearance. • Using Mendelian Randomization, we did not find a causal link between liver fat and hepatic insulin clearance. • The data showed a causal link between liver fat and whole-body insulin clearance. • Systemic inflammation and low HDL-cholesterol were causally associated with increased hepatic insulin clearance. [ABSTRACT FROM AUTHOR]