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Adipocyte and Cell Biology

In severe obesity, subcutaneous adipose tissue cell-derived cytokines are early markers of impaired glucose tolerance and are modulated by quercetin

Abstract

Background

Excessive adiposity provides an inflammatory environment. However, in people with severe obesity, how systemic and local adipose tissue (AT)-derived cytokines contribute to worsening glucose tolerance is not clear.

Methods

Ninty-two severely obese (SO) individuals undergoing bariatric surgery were enrolled and subjected to detailed clinical phenotyping. Following an oral glucose tolerance test, participants were included in three groups, based on the presence of normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or type 2 diabetes (T2D). Serum and subcutaneous AT (SAT) biopsies were obtained and mesenchymal stem cells (MSCs) were isolated, characterized, and differentiated in adipocytes in vitro. TNFA and PPARG mRNA levels were determined by qRT-PCR. Circulating, adipocyte- and MSC-released cytokines, chemokines, and growth factors were assessed by multiplex ELISA.

Results

Serum levels of IL-9, IL-13, and MIP-1β were increased in SO individuals with T2D, as compared with those with either IGT or NGT. At variance, SAT samples obtained from SO individuals with IGT displayed levels of TNFA which were threefold higher compared to those with NGT, but not different from those with T2D. Elevated levels of TNFα were also found in differentiated adipocytes, isolated from the SAT specimens of individuals with IGT and T2D, compared to those with NGT. Consistent with the pro-inflammatory milieu, IL-1β and IP-10 secretion was significantly higher in adipocytes from individuals with IGT and T2D. Moreover, increased levels of TNFα, both mRNA and secreted protein were detected in MSCs obtained from IGT and T2D, compared to NGT SO individuals. Exposure of T2D and IGT-derived MSCs to the anti-inflammatory flavonoid quercetin reduced TNFα levels and was paralleled by a significant decrease of the secretion of inflammatory cytokines.

Conclusion

In severe obesity, enhanced SAT-derived inflammatory phenotype is an early step in the progression toward T2D and maybe, at least in part, attenuated by quercetin.

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Fig. 1: SAT inflammation.
Fig. 2: Adipocyte-secreted cytokines and chemokines.
Fig. 3: MSC inflammation.
Fig. 4: Quercetin effect on MSC inflammation.

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Acknowledgements

The authors wish to thank Dr. Virginia Tagliamonte, Dr. Vincenzo Cosimato, and Dr. Aniello Rainone involved in patient enrollment and clinical phenotyping and in the management of the clinical records.

Funding

This work was supported by the Regione Campania POR FESR 2014–2020–Objective 1.2.—Realization of Technology Platform to fight oncologic diseases (RARE PLAT NET, SATIN, and COEPICA Projects) and by the Italian Association for the Cancer Research—AIRC (grant IG19001).

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VE: conceptualization, investigation, data curation, formal analysis, writing—original draft, writing—review & editing. MRA: conceptualization, investigation, data curation. DL: investigation, methodology. GP: investigation. ML: investigation, formal analysis. SC: investigation, writing—review & editing. MA: investigation. AM: data curation. VP: investigation. PF: conceptualization, supervision. CM: funding acquisition, supervision. DB: data curation, formal analysis. DT: project administration, supervision. FB: funding acquisition, resources. PF: conceptualization; funding acquisition; project administration; resources; supervision, writing—original draft; writing—review & editing.

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Correspondence to Pietro Formisano.

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D’Esposito, V., Ambrosio, M.R., Liguoro, D. et al. In severe obesity, subcutaneous adipose tissue cell-derived cytokines are early markers of impaired glucose tolerance and are modulated by quercetin. Int J Obes (2021). https://doi.org/10.1038/s41366-021-00850-1

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