Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI

Cell Rep Med. 2021 Mar 30;2(4):100226. doi: 10.1016/j.xcrm.2021.100226. eCollection 2021 Apr 20.

Authors

Birgitta W van der Kolk¹, Sina Saari¹, Alen Lovric^{2

3}, Muhammad Arif², Marcus Alvarez⁴, Arthur Ko⁵, Zong Miao^{4

6}, Navid Sahebekhtiari¹, Maheswary Muniandy¹, Sini Heinonen¹, Ali Oghabian¹, Riikka Jokinen¹, Sakari Jukarainen⁷, Antti Hakkarainen⁸, Jesper Lundbom^{8

9}, Juho Kuula^{8

10}, Per-Henrik Groop^{11

12

13

14}, Taru Tukiainen⁷, Nina Lundbom⁸, Aila Rissanen¹, Jaakko Kaprio⁷, Evan G Williams¹⁵, Nicola Zamboni¹⁵, Adil Mardinoglu^{2

16}, Päivi Pajukanta^{4

6

17}, Kirsi H Pietiläinen^{1

18}

Affiliations

¹ Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
² Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.
³ Division of Clinical Physiology, Department of Laboratory Medicine, Karolinska Institutet and Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.
⁴ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁶ Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA.
⁷ Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
⁸ HUS Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁹ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany.
¹⁰ Public Health Promotion Unit, National Institute for Health and Welfare, Helsinki, Finland.
¹¹ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
¹² Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹³ Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
¹⁴ Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
¹⁵ Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
¹⁶ Centre for Host-Microbiome Interactions, Dental Institute, King's College London, London, UK.
¹⁷ Institute for Precision Health, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁸ Obesity Center, Abdominal Center, Helsinki University Hospital, Helsinki, Finland.

Abstract

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.

Keywords: adipose tissue; genome-scale metabolic models; metabolomics; multiomics; obesity; proteomics; skeletal muscle; transcriptomics; twins.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Twin Study

MeSH terms

Adipocytes / metabolism
Adipose Tissue / metabolism*
Body Mass Index*
Inflammation / metabolism
Insulin Resistance / physiology
Mitochondria / metabolism
Muscle, Skeletal / metabolism*
Muscle, Skeletal / pathology
Obesity / metabolism*
Subcutaneous Fat / metabolism
Twins, Monozygotic / genetics

Abstract

Publication types

MeSH terms

Grants and funding