Insulin resistance rewires the metabolic gene program and glucose utilization in human white adipocytes
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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 journal › Journal article › peer-review
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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