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

Research output: Contribution to journalJournal articlepeer-review

Standard

Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. / Isidor, Marie S.; Dong, Wentao; Servin-Uribe, Rogelio I.; Villarroel, Julia; Altıntaş, Ali; Ayala-Sumuano, J. Tonatiuh; Varela-Echavarría, Alfredo; Barrès, Romain; Stephanopoulos, Gregory; Macotela, Yazmín; Emanuelli, Brice.

In: International Journal of Obesity, Vol. 46, No. 3, 2022, p. 535-543.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Isidor, MS, Dong, W, Servin-Uribe, RI, Villarroel, J, Altıntaş, A, Ayala-Sumuano, JT, Varela-Echavarría, A, Barrès, R, Stephanopoulos, G, Macotela, Y & Emanuelli, B 2022, 'Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes', International Journal of Obesity, vol. 46, no. 3, pp. 535-543. https://doi.org/10.1038/s41366-021-01021-y

APA

Isidor, M. S., Dong, W., Servin-Uribe, R. I., Villarroel, J., Altıntaş, A., Ayala-Sumuano, J. T., Varela-Echavarría, A., Barrès, R., Stephanopoulos, G., Macotela, Y., & Emanuelli, B. (2022). Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. International Journal of Obesity, 46(3), 535-543. https://doi.org/10.1038/s41366-021-01021-y

Vancouver

Isidor MS, Dong W, Servin-Uribe RI, Villarroel J, Altıntaş A, Ayala-Sumuano JT et al. Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. International Journal of Obesity. 2022;46(3):535-543. https://doi.org/10.1038/s41366-021-01021-y

Author

Isidor, Marie S. ; Dong, Wentao ; Servin-Uribe, Rogelio I. ; Villarroel, Julia ; Altıntaş, Ali ; Ayala-Sumuano, J. Tonatiuh ; Varela-Echavarría, Alfredo ; Barrès, Romain ; Stephanopoulos, Gregory ; Macotela, Yazmín ; Emanuelli, Brice. / Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes. In: International Journal of Obesity. 2022 ; Vol. 46, No. 3. pp. 535-543.

Bibtex

@article{c83ee348eae74016b5304003256e78f8,
title = "Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes",
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 towhich it affects adipose metabolic functions remain incompletely characterized.METHODS: We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceralwhite adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulinsensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming andglucose utilization using 13C-isotopic glucose tracing.RESULTS: We found that gene expression associated with impaired glucose and lipid metabolism and inflammation representedthe strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in maturehuman white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functionssuch as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucosemetabolism, 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 ofkey metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation inadipose dysfunction in humans.",
author = "Isidor, {Marie S.} and Wentao Dong and Servin-Uribe, {Rogelio I.} and Julia Villarroel and Ali Altınta{\c s} and Ayala-Sumuano, {J. Tonatiuh} and Alfredo Varela-Echavarr{\'i}a and Romain Barr{\`e}s and Gregory Stephanopoulos and Yazm{\'i}n Macotela and Brice Emanuelli",
year = "2022",
doi = "10.1038/s41366-021-01021-y",
language = "English",
volume = "46",
pages = "535--543",
journal = "International Journal of Obesity",
issn = "0307-0565",
publisher = "nature publishing group",
number = "3",

}

RIS

TY - JOUR

T1 - Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes

AU - Isidor, Marie S.

AU - Dong, Wentao

AU - Servin-Uribe, Rogelio I.

AU - Villarroel, Julia

AU - Altıntaş, Ali

AU - Ayala-Sumuano, J. Tonatiuh

AU - Varela-Echavarría, Alfredo

AU - Barrès, Romain

AU - Stephanopoulos, Gregory

AU - Macotela, Yazmín

AU - Emanuelli, Brice

PY - 2022

Y1 - 2022

N2 - 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 towhich it affects adipose metabolic functions remain incompletely characterized.METHODS: We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceralwhite adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulinsensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming andglucose utilization using 13C-isotopic glucose tracing.RESULTS: We found that gene expression associated with impaired glucose and lipid metabolism and inflammation representedthe strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in maturehuman white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functionssuch as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucosemetabolism, 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 ofkey metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation inadipose dysfunction in humans.

AB - 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 towhich it affects adipose metabolic functions remain incompletely characterized.METHODS: We interrogated the transcriptional adaptation to increased adiposity in association with insulin resistance in visceralwhite adipose tissue from lean men, or men presenting overweight/obesity (BMI from 19 to 33) and discordant for insulinsensitivity. In human adipocytes in vitro, we investigated the direct contribution of IR in altering metabolic gene programming andglucose utilization using 13C-isotopic glucose tracing.RESULTS: We found that gene expression associated with impaired glucose and lipid metabolism and inflammation representedthe strongest association with systemic insulin resistance, independently of BMI. In addition, we showed that inducing IR in maturehuman white adipocytes was sufficient to reprogram the transcriptional profile of genes involved in important metabolic functionssuch as glycolysis, the pentose phosphate pathway and de novo lipogenesis. Finally, we found that IR induced a rewiring of glucosemetabolism, 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 ofkey metabolic genes and impairing the metabolic processes of glucose utilization, and reveal a role for metabolic adaptation inadipose dysfunction in humans.

U2 - 10.1038/s41366-021-01021-y

DO - 10.1038/s41366-021-01021-y

M3 - Journal article

C2 - 34799672

VL - 46

SP - 535

EP - 543

JO - International Journal of Obesity

JF - International Journal of Obesity

SN - 0307-0565

IS - 3

ER -

ID: 285263821