Abdominal Subcutaneous Adipose Tissue Gene Expression in Relation to Tissue-Specific Insulin Resistance in Human Obesity - European Medical Journal

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Abdominal Subcutaneous Adipose Tissue Gene Expression in Relation to Tissue-Specific Insulin Resistance in Human Obesity

2 Mins
Diabetes
Authors:
†Birgitta W. van der Kolk,1 †Marianthi Kalafati,2,3 Michiel Adriaens,3 Marleen M.J. van Greevenbroek,4 Nicole Vogelzangs,3,5 Wim H.M. Saris,1 Arne Astrup,6 Armand Valsesia,7 Dominique Langin,8,9 Carla J.H. van der Kallen,4 Simone J.P.M Eussen,5 Casper G. Schalkwijk,4 Coen D.A. Stehouwer,4 Gijs H. Goossens,1 Ilja C.W. Arts,3,5 Johan W.E. Jocken,1 ‡Chris T. Evelo,2,3 *‡Ellen E. Blaak1

1. Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
2. Department of Bioinformatics-BiGCaT, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
3. Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, Netherlands
4. Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
5. Department of Epidemiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
6. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
7. Nestlé Institute of Health Sciences, Lausanne, Switzerland
8. Institut National de la Santé et de la Recherche Médicale (Inserm), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France
9. University of Toulouse, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Paul Sabatier University, Toulouse, France
*Correspondence to [email protected]

Disclosure:

Dr Valsesia is a full-time employee at Nestlé Institute of Health Sciences SA. Dr Saris reports having received research support from Nestlé, DSM, Unilever, Nutrition et Sante, Danone, GSK, Novartis, and Novo Nordisk; he is an unpaid scientific advisor for the International Life Science Institute, ILSI Europe. Dr Astrup reports grants and personal fees from Gelesis; personal fees from Acino, BioCare Copenhagen, Dutch Beer Institute, Groupe Éthique et Santé, IKEA Food Scientific Health Advisory Board, McCain Foods Limited, Navamedic, Novo Nordisk, Pfizer, Saniona, Weight Watchers, and Zaluvida;  and grants from DC-Ingredients Denmark, outside the submitted work. Dr Blaak receives grant support from DSM, Danone, Friesland Campina, Avebe, Sensus (partly within the context of public-private consortia), and Novartis. She is involved in several task forces/expert groups related to the International Life Science Institute, ILSI Europe. The remaining authors have declared no conflicts of interest.

Acknowledgements:

†co-first authors. ‡co-last authors.

Citation:
EMJ Diabet. ;6[1]:37-39. Abstract Review No. AR2.
Keywords:
Adipose tissue, hepatic insulin sensitivity, insulin resistance, low-grade inflammation, muscle insulin sensitivity, obesity, transcriptomics.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Obesity and being overweight are major risk factors for several diseases, including cardiovascular disease and Type 2 diabetes mellitus.1 Adipose tissue dysfunction, rather than excess fat mass per se, is frequently associated with the progression towards insulin resistance (IR).2 IR can develop simultaneously in multiple organs, but the severity may vary between organs. For instance, impaired fasting glucose and impaired glucose tolerance may represent distinct prediabetic phenotypes, which are characterised by more pronounced hepatic or muscle IR, respectively.3 Identification and quantification of metabolic anomalies in different IR phenotypes are important because they can provide directions for more personalised lifestyle or pharmacological interventions in the prevention and control of cardiometabolic diseases. Indeed, there is evidence from a post-hoc analysis that the response to nutritional intervention may depend on IR phenotype (e.g., being more insulin resistant at the level of the liver or skeletal muscle).4 Analysis of gene expression in subcutaneous adipose tissue (ScAT) may help to elucidate the pathways and mechanisms that link adipose tissue function to tissue-specific IR. Therefore, the presented study aimed to identify distinct transcriptome profiles of abdominal ScAT in relation to muscle or liver IR.

In this study, we identified abdominal ScAT transcriptome profiles in relation to liver or muscle IR by RNA sequencing in overweight and obese non-diabetic participants of the DiOGenes study (BMI >27 kg/m2; n=368). The tissue-specific IR phenotype was based on tertiles of the muscle insulin sensitivity index (MISI) and the hepatic IR index (HIRI), derived from a 5-point oral glucose tolerance test.5 Subsequently, the participants were classified at baseline into 4 groups: no-IR (n=186), muscle-IR (n=69), liver-IR (n=53), and muscle/liver-IR (n=60). ScAT RNA sequencing data were compared between groups using differential gene expression analysis (DESeq)2 and were adjusted for study centre, sex, BMI, and waist-to-hip ratio. We found that ScAT extracellular matrix organisation genes (e.g., collagens) were significantly upregulated in the liver-IR versus no-IR comparison (fold change [FC] >1.2; p<0.05). In muscle-IR versus no-IR comparison, inflammatory pathways were significantly changed with pronounced upregulation of chemokine and complement genes (FC >1.2; p<0.05).

Following up on the DiOGenes outcomes, the relationship between systemic low-grade inflammation and IR phenotype was studied in overweight and obese non-diabetic individuals of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (BMI >25 kg/m2 [n=325]) and Maastricht study (BMI >27 kg/m2 [n=792]), using linear regression analyses. The plasma low-grade inflammation score was inversely associated with MISI (CODAM: standardised-ß: -0.108, 95% confidence interval [CI]: 0.205; -0.011; p=0.028; Maastricht Study: standardised-ß: -0.131, 95% CI: 0.193; 0.068; p<0.001), while no association was observed with HIRI (CODAM: standardised-ß: 0.066; 95% CI: -0.032; 0.165; p=0.184; Maastricht Study: standardised-ß: 0.000, 95% CI: 0.064; 0.064; p=0.995). Importantly, the association between low-grade inflammation and MISI was adjusted for HIRI, and vice versa. We showed in these two independent cohorts that an increased systemic low-grade inflammation profile was specifically related to muscle IR.

In conclusion, we showed that hepatic and muscle IR were characterised by distinct abdominal ScAT transcriptome profiles. Extracellular matrix remodelling genes were upregulated in individuals with primarily hepatic IR, while inflammatory genes were significantly upregulated in primarily muscle IR individuals. An increased systemic low-grade inflammation profile was specifically related to muscle 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 personalised nutritional or lifestyle prevention strategies.

References
Pi-Sunyer X. The medical risks of obesity. Postgrad Med. 2015;121(6):21-33. Goossens GH. The metabolic phenotype in obesity: Fat  mass, body fat distribution, and adipose tissue function. Obes Facts. 2017;10(3):207-15. Stefan N et al. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol. 2016;4(9):789-98. Blanco-Rojo R et al. The insulin resistance phenotype (muscle or liver) interacts with the type of diet to determine changes in disposition index after 2 years of intervention: The CORDIOPREV-DIAB randomised clinical trial. Diabetologia. 2016;59(1):67-76. Abdul-Ghani MA et al. Muscle and liver insulin resistance indexes derived from the oral glucose tolerance test. Diabetes Care. 2007;30(1):89-94.

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