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

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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.
Original languageEnglish
JournalInternational Journal of Obesity
Issue number3
Pages (from-to)535-543
Publication statusPublished - 2022

ID: 285263821