Glucose tolerance and insulin sensitivity define adipocyte transcriptional programs in human obesity

R. Gerlini, L. Berti, J. Darr, M. Lassi, S. Brandmaier, L. Fritsche, F. Scheid, A. Böhm, A. Königsrainer, H. Grallert, H.U. Häring, M. Hrabě de Angelis, H. Staiger, R. Teperino

Obese individuals are at high risk of developing life-threatening co-morbidities. However, 10-25 % of obese people stay healthy. These individuals remain glucose tolerant and insulin sensitive, with normal blood pressure and a favorable lipid profile. Gerlini, Berti, and colleagues analyzed primary subcutaneous adipocytes from morbidly obese individuals discordant for metabolic health. They discovered that instead of insulin resistance, impaired glucose homeostasis is a major determinant of adipocyte transcriptional response. Furthermore, they identified 19 genetic associations with phenotypes of glucose homeostasis and/or body weight and composition.

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.