The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance

English version

Autoři: Zong Miao ^aff001; Marcus Alvarez ^aff001; Arthur Ko ^aff003; Yash Bhagat ^aff001; Elior Rahmani ^aff004; Brandon Jew ^aff002; Sini Heinonen ^aff005; Linda Liliana Muñoz-Hernandez ^aff006; Miguel Herrera-Hernandez ^aff009; Carlos Aguilar-Salinas ^aff006; Teresa Tusie-Luna ^aff010; Karen L. Mohlke ^aff011; Markku Laakso ^aff012; Kirsi H. Pietiläinen ^aff005; Eran Halperin ^aff001; Päivi Pajukanta ^aff001
Působiště autorů: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff001; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, California, United States of America ^aff002; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff003; Computer Science Department in the School of Engineering, UCLA, Los Angeles, California, United States of America ^aff004; Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland ^aff005; Unidad de Investigación en Enfermedades Metabólicas, Dirección de Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico ^aff006; Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico ^aff007; Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, México ^aff008; Departamento de Cirugía, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City, Mexico ^aff009; Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas UNAM / Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Mexico City, Mexico ^aff010; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America ^aff011; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland ^aff012; Obesity Center, Endocrinology, Abdominal Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland ^aff013; Department of Computational Medicine, UCLA, Los Angeles, California, United States of America ^aff014; Department of Anesthesiology and Perioperative Medicine, UCLA, Los Angeles, California, United States of America ^aff015; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America ^aff016
Vyšlo v časopise: The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009018
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009018

Souhrn

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10⁻³ and p = 3.1×10⁻²⁴). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10⁻⁵ in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals’ adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

Klíčová slova:

Adipose tissue – Body Mass Index – Forecasting – Gene expression – Genome-wide association studies – Insulin resistance – Obesity – Type 2 diabetes

Zdroje

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