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

Zong Miao, Marcus Alvarez, Arthur Ko, Yash Bhagat, Elior Rahmani, Brandon Jew, Sini Heinonen, Linda Liliana Muñoz-Hernandez, Miguel Herrera-Hernandez, Carlos Aguilar-Salinas, Teresa Tusie-Luna, Karen L. Mohlke, Markku Laakso, Kirsi H. Pietiläinen, Eran Halperin, Päivi Pajukanta*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 = 1.2×10−3 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.

Original languageEnglish
Article numbere1009018
JournalPLoS Genetics
Volume16
Issue number9 September
DOIs
StatePublished - Sep 2020
Externally publishedYes

Funding

FundersFunder number
GTEx08/14/ 2016, phs000424.v6.p1, 33934
National Science Foundation1705197
National Institutes of HealthHL-095056, U01 DK105561, HL-28481
Howard Hughes Medical InstituteF31HL127921
National Human Genome Research InstituteR01HG010505
American Heart Association19PRE34430112
University of California, Los Angeles
Helsingin Yliopisto
Helsingin ja Uudenmaan Sairaanhoitopiiri
Suomen Lääketieteen Säätiö
Academy of Finland272376, 315035, 266286, 314383
Signe ja Ane Gyllenbergin Säätiö
Sigrid Juséliuksen Säätiö
Novo Nordisk Fonden
Diabetestutkimussäätiö

    Fingerprint

    Dive into the research topics of 'The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance'. Together they form a unique fingerprint.

    Cite this