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


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: 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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