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The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance
- Source :
- PLoS Genetics, PLoS Genetics, Vol 16, Iss 9, p e1009018 (2020)
- Publication Year :
- 2019
-
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.<br />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.
- Subjects :
- Male
Cancer Research
Physiology
Adipose tissue
Gene Expression
Type 2 diabetes
QH426-470
Body Mass Index
Cohort Studies
0302 clinical medicine
Endocrinology
Mathematical and Statistical Techniques
Medical Conditions
Weight loss
Adipocytes
Medicine and Health Sciences
Prediabetes
Genetics (clinical)
Adiposity
2. Zero hunger
0303 health sciences
Statistics
1184 Genetics, developmental biology, physiology
ASSOCIATION
Genomics
Middle Aged
3. Good health
Type 2 Diabetes
SINGLE
Adipose Tissue
Physiological Parameters
Connective Tissue
Physical Sciences
MENDELIAN RANDOMIZATION
Female
medicine.symptom
Anatomy
Research Article
EXPRESSION
Adult
medicine.medical_specialty
MITOCHONDRIAL DYSFUNCTION
Endocrine Disorders
Subcutaneous Fat
WEIGHT-LOSS
Biology
Research and Analysis Methods
Prediabetic State
03 medical and health sciences
Insulin resistance
BETA-CELL FUNCTION
INFLAMMATION
Diabetes mellitus
Internal medicine
Mendelian randomization
medicine
Genetics
Genome-Wide Association Studies
Diabetes Mellitus
Humans
Obesity
Statistical Methods
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Endocrine Physiology
Body Weight
Biology and Life Sciences
Computational Biology
Human Genetics
medicine.disease
Genome Analysis
BODY-MASS INDEX
Biological Tissue
Diabetes Mellitus, Type 2
Metabolic Disorders
GLUCOSE-TOLERANCE
Insulin Resistance
030217 neurology & neurosurgery
Mathematics
Forecasting
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 16
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- PLoS genetics
- Accession number :
- edsair.doi.dedup.....9f6afd0b8512394740bc0cf1357038fa