Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans

Abstract

Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.

Chronic stress, epigenetics, and adipose tissue metabolism in the obese state

“…Moreover, whole-exome sequencing revealed one mutation in ADAMTSL3 that is associated with type II diabetes in a Japanese family [118]. It was also found to be differentially expressed in hepatic insulin resistant subjects [119]. Mutations in ADAMTSL3 has also been associated with plasma HDL level alteration in families with premature coronary artery disease and acute myocardial infarction [120].…”

Current metabolic perspective on malnutrition in obesity: towards more subgroup-based nutritional approaches?

“…A first question that has to be addressed then is whether these phenotypes are really distinct. We addressed this question by characterising the plasma metabolome (15) and lipidome (16) and adipose tissue transcriptome profiles (17) in individuals with either more pronounced hepatic IR or more pronounced muscle IR in the European multicentre DIOGenes trial in overweight and obese individuals (18) ; and used the Cohort on Diabetes and Atherosclerosis Maastricht (19) and the Maastricht study, a large population-based cohort in the Maastricht area (20) as validation cohorts. Based on a 5 or 7-points oral glucose tolerance test with insulin and glucose concentrations we estimated hepatic IR and skeletal muscle insulin sensitivity indices (HIRI and MISI, respectively) as previously described and validated against a hyperinsulinemic clamp by Abdul Ghani et al (21) , and optimised for the MISI calculation by means of cubic splining by O'Donovan et al (22) .…”

“…This is in line with studies in obese men and women using hyperinsulinemic euglycemic clamp techniques (23) . Individuals with HIRI or combined HIRI/MISI in general have higher plasma TAG and a larger waist (15)(16)(17) .…”

“…Previous studies investigating the subcutaneous adipose tissue (ScAT) transcriptome have found an upregulation of ScAT inflammatory pathways and a downregulation of lipid metabolism pathways and/or mitochondrial respiratory pathways in individuals with whole body IR v. BMI-matched controls (32) or in obese women with IR as compared to lean insulin sensitive women (33) . To investigate whether differential ScAT transcriptome profiles were related to more pronounced muscle or hepatic IR, we analysed baseline RNA sequencing profiles in 368 individuals in overweight and obese individuals of the DIOGenes study and we subsequently validated mechanisms related to the systemic inflammatory profile in two independent cohorts Cohort on Diabetes and Atherosclerosis Maastricht and the Maastricht study (17) . We showed that an altered extracellular matrix remodelling gene expression profile in abdominal ScAT was present in overweight and obese individuals with pronounced hepatic IR.…”

“…Personalisation based on microbial composition and phenotype has received increased attention, and in the following paragraphs this will be addressed targeting the microbial functionality with emphasis on the production of SCFA. Linear mixed model (Diogenes) or regression (Maastricht study) analyses with metabolite/lipid/gene expression as a dependent variable, hepatic insulin resistance indices/muscle insulin sensitivity indices as an independent variable, adjusted for BMI, waist:hip ratio and study centre included as a random effect (Diogenes), based on (15)(16)(17) . ScAT, subcutaneous adipose tissue; ECM, extracellular matrix.…”