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Adipocyte and Cell Biology

Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes

International Journal of Obesity volume 46, pages 535–543 (2022)Cite this article

Subjects

Abstract

Background

In obesity, adipose tissue dysfunction resulting from excessive fat accumulation leads to systemic insulin resistance (IR), the underlying alteration of Type 2 Diabetes. The specific pathways dysregulated in dysfunctional adipocytes and the extent to which it affects adipose metabolic functions remain incompletely characterized.

Methods

We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceral white adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulin sensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming and glucose utilization using 13C-isotopic glucose tracing.

Results

We found that gene expression associated with impaired glucose and lipid metabolism and inflammation represented the strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in mature human white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functions such as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucose metabolism, with higher incorporation of glucose into citrate, but not into downstream metabolites within the TCA cycle.

Conclusions

Collectively, our data highlight the importance of obesity-derived insulin resistance in impacting the expression of key metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation in adipose dysfunction in humans.

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Fig. 1: Systemic insulin resistance is associated with a gene expression signature of perturbed glucose and lipid metabolism in human visceral adipose tissue.
Fig. 2: Induction of insulin resistance in human mature white adipocytes.
Fig. 3: IR induces a global decrease in gene expression of enzymes involved in glucose metabolism.
Fig. 4: IR impairs insulin-stimulated glucose uptake, but not mitochondrial respiration.
Fig. 5: IR rearranges glucose utilization in human white adipocytes.

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Acknowledgements

We thank Xarubet Ruiz-Herrera, Samuel A.J. Trammel and Patricia S. S. Petersen for technical assistance, Juleen R. Zierath and the members of the Emanuelli group for discussions.

Funding

This work was supported by internal funding from the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900). MSI received an EFSD Albert Renold Travel Fellowship. GS and WD were supported by NIH R01 CA160458. YM was funded by CONACYT 261168 and 284771. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; nor in the writing of the report; and in the decision to submit the article for publication.

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Authors and Affiliations

  1. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Marie S. Isidor, Julia Villarroel, Ali Altıntaş, Romain Barrès & Brice Emanuelli

  2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, USA

    Marie S. Isidor, Wentao Dong & Gregory Stephanopoulos

  3. Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, 76230, Querétaro, México

    Rogelio I. Servin-Uribe, J. Tonatiuh Ayala-Sumuano, Alfredo Varela-Echavarría & Yazmín Macotela

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  1. Marie S. Isidor
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Contributions

MSI, YM, BE: study conception and design, data interpretation. MSI, WD, RISU: experimentation. MSI, RISU, JTAS, AVE, JV, AA, RB: data analysis. GS: supervision of metabolic tracing study. MSI, WD, YM, BE: manuscript preparation. BE: overall supervision. All authors reviewed and approved the manuscript.

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Correspondence to Brice Emanuelli.

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Isidor, M.S., Dong, W., Servin-Uribe, R.I. et al. Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. Int J Obes 46, 535–543 (2022). https://doi.org/10.1038/s41366-021-01021-y

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