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

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Miao , Z , Alvarez , M , Ko , A , Bhagat , Y , Rahmani , E , Jew , B , Heinonen , S , Munoz-Hernandez , L L , Herrera-Hernandez , M , Aguilar-Salinas , C , Tusie-Luna , T , Mohlke , K L , Laakso , M , Pietiläinen , K H , Halperin , E & Pajukanta , P 2020 , ' The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance ' , PLoS Genetics , vol. 16 , no. 9 , 1009018 . https://doi.org/10.1371/journal.pgen.1009018

Title: The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance
Author: Miao, Zong; Alvarez, Marcus; Ko, Arthur; Bhagat, Yash; Rahmani, Elior; Jew, Brandon; Heinonen, Sini; Munoz-Hernandez, Linda Liliana; Herrera-Hernandez, Miguel; Aguilar-Salinas, Carlos; Tusie-Luna, Teresa; Mohlke, Karen L.; Laakso, Markku; Pietiläinen, Kirsi H.; Halperin, Eran; Pajukanta, Päivi
Contributor: University of Helsinki, CAMM - Research Program for Clinical and Molecular Metabolism
University of Helsinki, HUS Abdominal Center
Date: 2020-09
Language: eng
Number of pages: 23
Belongs to series: PLoS Genetics
ISSN: 1553-7404
URI: http://hdl.handle.net/10138/320488
Abstract: 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 = 1.2x10(-3)and p = 3.1x10(-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 Author summary Obesity is a global health epidemic predisposing to type 2 diabetes (T2D) and other cardiometabolic disorders. Previous studies have shown that obesity has a causal effect on T2D; however, it remains unknown whether obesity causes prediabetes and insulin resistance already in non-diabetic individuals. By utilizing almost half a million individuals from the UK Biobank and the Finnish METSIM cohort, we identified a significant causal effect of obesity on prediabetes and insulin resistance among the non-diabetic individuals. Next, we investigated the role of subcutaneous adipose tissue in these obesogenic effects. We discovered that the adipose mitochondrial gene expression and body fat percent are independently associated with insulin resistance after adjusting for the tissue heterogeneity. For the latter, we estimated the adipose cell type proportions by utilizing single-nucleus RNA sequencing of frozen adipose tissue biopsies. Moreover, we established a prediction model to estimate insulin resistance using body fat percent and adipose RNA-sequencing data, which enlightens the importance of adipose tissue in insulin resistance and provides a helpful tool to impute the insulin resistance for existing adipose RNA-sequencing cohorts. Overall, we discover the potential causal effect of obesity on prediabetes and insulin resistance and the key role of adipose tissue in insulin resistance.
Subject: BETA-CELL FUNCTION
BODY-MASS INDEX
MITOCHONDRIAL DYSFUNCTION
MENDELIAN RANDOMIZATION
GLUCOSE-TOLERANCE
WEIGHT-LOSS
ASSOCIATION
INFLAMMATION
EXPRESSION
SINGLE
1184 Genetics, developmental biology, physiology
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