The dual nature of DNA damage response in obesity and bariatric surgery-induced weight loss

The dual nature of DNA damage response in obesity and bariatric surgery-induced weight loss

This novel study applies targeted functional proteomics to examine tissues and cells obtained from a cohort of individuals with severe obesity who underwent bariatric surgery (BS), using a Reverse-Phase Protein Array (RPPA). In obese individuals, visceral adipose tissue (VAT), but not subcutaneous a...

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Bibliographic Details
Published in:Cell death & disease Vol. 15; no. 9; pp. 664 - 11
Main Authors: Escobar Marcillo, David Israel, Guglielmi, Valeria, Privitera, Grete Francesca, Signore, Michele, Simonelli, Valeria, Manganello, Federico, Dell’Orso, Ambra, Laterza, Serena, Parlanti, Eleonora, Pulvirenti, Alfredo, Marcon, Francesca, Siniscalchi, Ester, Fertitta, Veronica, Iorio, Egidio, Varì, Rosaria, Nisticò, Lorenza, Valverde, Mahara, Sbraccia, Paolo, Dogliotti, Eugenia, Fortini, Paola
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 11-09-2024
Springer Nature B.V
Nature Publishing Group
Subjects:
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Adipose tissue
Adult
Antibodies
Bariatric Surgery - methods
Biochemistry
Biomedical and Life Sciences
Body fat
Body weight loss
Cell Biology
Cell Culture
Cellular stress response
CHK1 protein
DNA Damage
Female
Gastrointestinal surgery
Histone H2A
Humans
Immunology
Intra-Abdominal Fat - metabolism
Leukocytes (mononuclear)
Leukocytes, Mononuclear - metabolism
Life Sciences
Male
Metabolic rate
Metabolism
Middle Aged
Mitochondria - metabolism
Obesity
Obesity - metabolism
Obesity - surgery
Peripheral blood mononuclear cells
Protein arrays
Proteomics
Senescence
Surgery
Survivin
TOR protein
Weight control
Weight Loss
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Summary:This novel study applies targeted functional proteomics to examine tissues and cells obtained from a cohort of individuals with severe obesity who underwent bariatric surgery (BS), using a Reverse-Phase Protein Array (RPPA). In obese individuals, visceral adipose tissue (VAT), but not subcutaneous adipose tissue (SAT), shows activation of DNA damage response (DDR) markers including ATM, ATR, histone H2AX, KAP1, Chk1, and Chk2, alongside senescence markers p16 and p21. Additionally, stress-responsive metabolic markers, such as survivin, mTOR, and PFKFB3, are specifically elevated in VAT, suggesting both cellular stress and metabolic dysregulation. Conversely, peripheral blood mononuclear cells (PBMCs), while exhibiting elevated mTOR and JNK levels, did not present significant changes in DDR or senescence markers. Following BS, unexpected increases in phosphorylated ATM, ATR, and KAP1 levels, but not in Chk1 and Chk2 nor in senescence markers, were observed. This was accompanied by heightened levels of survivin and mTOR, along with improvement in markers of mitochondrial quality and health. This suggests that, following BS, pro-survival pathways involved in cellular adaptation to various stressors and metabolic alterations are activated in circulating PBMCs. Moreover, our findings demonstrate that the DDR has a dual nature. In the case of VAT from individuals with obesity, chronic DDR proves to be harmful, as it is associated with senescence and chronic inflammation. Conversely, after BS, the activation of DDR proteins in PBMCs is associated with a beneficial survival response. This response is characterized by metabolic redesign and improved mitochondrial biogenesis and functionality. This study reveals physiological changes associated with obesity and BS that may aid theragnostic approaches.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-024-06922-0