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

Kolk, Birgitta W. van der; Saari, Sina; Lovrić, Alen; Arif, Muhammad; Alvarez, Marcus; Ko, Arthur; Zong, Min‐Hua; Sahebekhtiari, Navid; Muniandy, Maheswary; Heinonen, Sini; Oghabian, Ali; Jokinen, Riikka; Jukarainen, Sakari; Hakkarainen, Antti; Lundbom, Jesper; Kuula, Juho; Groop, Per Henrik; Tukiainen, Taru; Lundbom, Nina; Rissanen, Aila; Kaprio, Jaakko; Williams, Evan G.; Zamboni, Nicola; Mardinoğlu, Adil; Pajukanta, Päivi; Pietiläinen, Kirsi H.

doi:10.1016/j.xcrm.2021.100226

Cited by 43 publications

(41 citation statements)

References 80 publications

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“…Spermidine is generally thought to be reduced with aging, but the authors speculated that higher spermidine concentrations in frail subjects may reflect differences in underlying neuromuscular disorders or oxidative stress. Finally, similar to our data uncovering metabolic signatures of unhealthy aging trajectories, linoleate and alpha-tocopherol were both reported to be elevated in human vastus lateralis muscles from overweight twins after a 12 h fast [39].…”

Section: Discussionsupporting

confidence: 88%

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

Tokarz

Möller

Artati

et al. 2021

IJMS

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Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a ‘rewired’ metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.

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Section: Discussionsupporting

confidence: 88%

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

Tokarz

Möller

Artati

et al. 2021

IJMS

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“…Our co-expression analysis of transcriptomics data captured shared modules of genes associated with both obesity and T2D in the adipose tissues, supporting that obesity can contribute to the development of T2D at the transcription level. Importantly, immune response-related pathways were upregulated whereas the lipid metabolism and mitochondrial pathways were downregulated, which is in line with previous findings in human and rodent models 8,60,72 . Indeed, the adipose tissues in obesity and diabetes are infiltrated with immune cells and increase secretion of proinflammatory cytokines 47 .…”

Section: Discussionsupporting

confidence: 91%

“…However, the molecular mechanisms of how these loci regulate gene expression and impact protein function remain poorly understood. Previous studies have investigated the transcriptomes or proteomes of obese patients in tissues including blood 3,4 , adipose tissues [5][6][7][8] , liver 9 , muscle 8,10,11 , breast 12 , granulosa cells 13 , and sperm 14 . However, these studies have yielded inconclusive and sometimes conflicting results about obesity-related molecular changes 15 .…”

Section: Introductionmentioning

confidence: 99%

A Transcriptomic and Proteomic Atlas of Obesity and Type 2 Diabetes in Cynomolgus Monkeys

Zhang

Lü²,

Homann

et al. 2021

Preprint

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Obesity and type 2 diabetes (T2D) remain major global healthcare challenges and developing therapeutics necessitate using nonhuman primate models. Here, we present transcriptomic and proteomic analyses of all the major organs of cynomolgus monkeys with spontaneous obesity or T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose tissues of individuals with obesity, while extensive expression perturbations among T2D individuals are observed in many tissues, such as the liver, kidney, brain, and heart. Immune response-related pathways are upregulated in obesity and T2D, whereas metabolism and mitochondrial pathways are downregulated. Incorporating human single-cell RNA sequencing findings corroborates the role of macrophages and monocytes in obesity. Moreover, we highlight some potential therapeutic targets including SLC2A1 and PCSK1 in obesity as well as SLC30A8 and SLC2A2 in T2D. Our findings provide insights into tissue-specific molecular foundations of obesity and T2D and reveal the mechanistic links between these two metabolic disorders.

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“…Adipocyte diameters were automatically measured from the images using a custom algorithm for ImageJ (ImageJ 1.42q/ Java 1. 6.0 10 32-bit; https://github.com/birgittavdkolk/vanderkolk_etal_2021) (van der Kolk et al, 2021) which preprocessed the image to enhance the borders of the adipocytes and then used a circle-detection algorithm to identify the cells. The algorithm was tuned to identify the adipocytes taken using the standardized microscope settings and validated against 2000 manually measured diameters from 20 pictures (r = 0.85, p < 0.001).…”

Section: Methods Detailsmentioning

confidence: 99%

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation and gut microbiota composition in a twin study

Lapatto

Kuusela

Heikkinen

et al. 2022

Preprint

Self Cite

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SummaryNAD+ precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have failed to report positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twins from 22 BMI-discordant monozygotic pairs were supplemented with an escalating dose of NR (250-1000 mg/day) for 5 months (clinicaltrials.gov entry NCT03951285). NR improved blood and tissue NAD+ metabolism, muscle mitochondrial number, myoblast differentiation and gut microbiota composition independent of BMI. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.

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

Cited by 43 publications

References 80 publications

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

A Transcriptomic and Proteomic Atlas of Obesity and Type 2 Diabetes in Cynomolgus Monkeys

Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation and gut microbiota composition in a twin study

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