Hypoxia decreases insulin signaling pathways in adipocytes.
Open accessAbstract
OBJECTIVE—Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes. RESEARCH DESIGN AND METHODS—The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O2) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport. RESULTS—In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1α or -2α or activation of HIF transcription factor with CoCl2 mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1α and -2α by small interfering RNA inhibited it. CONCLUSIONS—We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.
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Written from the paper’s full text.
TL;DR
Hypoxia (1% O₂) inhibits insulin signaling in human and murine adipocytes, decreasing insulin receptor, IRS-1/2, PKB, AS160, and S6K phosphorylation and blunting insulin-stimulated glucose transport. This insulin-resistant state is reversible upon reoxygenation and depends on HIF-1α/HIF-2α transcription factors.
Key findings
- Hypoxia inhibited insulin-induced insulin receptor autophosphorylation by about 50% and nearly completely inhibited insulin-stimulated glucose transport in 3T3-L1 adipocytes; normoxic insulin induced a 10-fold increase in glucose transport, and reoxygenation restored insulin response after 45 min.
- Hypoxia also reduced IRS-1 and IRS-2 tyrosine phosphorylation, PKB phosphorylation, AS160 phosphorylation, and S6K phosphorylation in murine adipocytes, and inhibited insulin receptor and IRS tyrosine phosphorylation in human adipocytes.
- The inhibition was independent of protein tyrosine phosphatases: total phosphatase activity did not differ significantly between normoxia and hypoxia, and vanadate or H₂O₂ did not restore insulin receptor phosphorylation under hypoxia.
- HIF signaling was necessary and sufficient: CoCl₂ or HIF-1α/HIF-2α overexpression mimicked the inhibition, while siRNA knockdown of HIF-1α and -2α (57 ± 3% inhibition) partially restored insulin receptor tyrosine phosphorylation. Hypoxia also increased glycerol release (48 ± 2 vs. 4 ± 0.7 μg/ml) and IL-6 secretion (2.1 ± 0.28 vs. 0.1 ± 0.02 ng/ml), but conditioned media from hypoxic adipocytes did not reproduce the insulin signaling inhibition.
Methods
- Human and murine adipocytes (3T3-L1 and human preadipocytes) were incubated under normoxia or hypoxia (1% O₂) for 16 h, or 24 h for human adipocytes, with or without insulin stimulation; HEK-293 cells were used for HIF-1α/HIF-2α overexpression.
- Signaling was assessed by Western blot and immunoprecipitation for phosphorylation of insulin receptor, IRS-1/2, PKB, AS160, and S6K; glucose transport was measured with 2-[³H]deoxyglucose; ROS with DCFH-DA; glycerol and IL-1β/IL-6 by assay kits; PTPase activity was measured anaerobically.
- Statistical differences were analyzed by Student’s t test and considered significant at P ≤ 0.05.
Limitations
- Stated by the paper: the mechanism is not fully understood; the authors cannot exclude that HIF proteins act independently of transcription; ROS effects on insulin receptor tyrosine kinase activity are difficult to test because ROS inhibitors themselves affect insulin receptor activity; and the in vitro adipocyte system does not capture macrophage-derived cytokines in vivo.
- Evident from the text: HIF-1α/-2α knockdown was only partial (57 ± 3%) and produced only partial restoration of insulin signaling; glucose transport and most mechanistic experiments were performed in 3T3-L1 adipocytes, with human adipocytes used mainly for signaling; and no in vivo obesity model was used to test whether hypoxia directly causes adipose insulin resistance.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
0 of 9 cited sources checked · 0 supported · 0 flagged
- Findingown data
Vanadate does not restore insulin-stimulated tyrosine phosphorylation of insulin receptor in hypoxia.
“Although vanadate increased the level of protein tyrosine phosphorylation in normoxia, because of the inhibition of cellular phosphatases, it did not restore the ability of insulin to stimulate the tyrosine phosphorylation of its receptor in hypoxia.”
Quote in the paperSubstantial claim - Findingown data
3T3-L1 adipocytes incubated in 21% or 7% O2 respond similarly to insulin stimulation.
“Adipocytes incubated in 21% or 7% O2 responded similarly to insulin stimulation (Online Appendix 1, available at http://dx.doi.org/10.2337/db08-0457).”
Quote in the paperNot a substantial claim - Findingown data
CoCl2 induces HIF-2α expression in 3T3-L1 adipocytes.
“CoCl2 induced HIF-2α expression.”
Quote in the paperSubstantial claim - Findingown data
In human adipocytes, hypoxia inhibits insulin-induced insulin receptor and IRS tyrosine phosphorylation.
“Hypoxia stimulated HIF-1α and -2α protein expression and inhibited insulin-induced insulin receptor and IRS tyrosine phosphorylation.”
Quote in the paperSubstantial claim - Findingown data
siRNA-mediated downregulation of HIF-1α and -2α partially restores insulin-stimulated tyrosine phosphorylation of insulin receptor in hypoxia.
“This was accompanied by a partial restoration of the ability of insulin to stimulate the tyrosine phosphorylation of its receptor.”
Quote in the paperSubstantial claim
- Findingown data
CoCl2 inhibits S6K phosphorylation in response to insulin.
“In parallel, CoCl2 inhibited the phosphorylation of S6K in response to insulin.”
Quote in the paperSubstantial claim - Findingown data
In 3T3-L1 adipocytes, hypoxia inhibits IRS-1 and IRS-2 tyrosine phosphorylation.
“Specific immunoprecipitation of IRS-1 or -2 revealed that hypoxia inhibited IRS-1 and -2 tyrosine phosphorylation (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
In 3T3-L1 adipocytes, hypoxia inhibits S6K phosphorylation in response to insulin.
“Moreover, hypoxia inhibited S6 kinase (S6K) phosphorylation in response to insulin (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
Hypoxia induces glycerol release in 3T3-L1 adipocytes (48 μg/ml ± 2 in hypoxia vs 4 μg/ml ± 0.7 in normoxia).
“Hypoxia induced a release of glycerol in the media (48 μg/ml ± 2 in hypoxia compared with 4 μg/ml ± 0.7 in normoxia).”
Quote in the paperSubstantial claim - Findingcitation
IL-6 concentrations increased by hypoxia are inferior to those described to inhibit insulin signaling in adipocytes (2 vs. 20 ng/ml).
“Analysis of conditioned media revealed that IL-6 protein secretion was increased by hypoxia but at concentrations inferior to that described to inhibit the insulin signaling pathway in adipocytes (2 vs. 20 ng/ml) (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Rotter V, Nagaev I, Smith U: Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784,2003 source
Not checked in the free run.
- Findingown data
In human adipocytes, hypoxia stimulates HIF-1α and -2α protein expression.
“Hypoxia stimulated HIF-1α and -2α protein expression and inhibited insulin-induced insulin receptor and IRS tyrosine phosphorylation.”
Quote in the paperNot a substantial claim - Findingown data
Hypoxia increases IL-6 secretion from 3T3-L1 adipocytes (0.1 ± 0.02 ng/ml normoxia to 2.1 ± 0.28 ng/ml after 16 h hypoxia).
“IL-6 secretion was increased from 0.1 ± 0.02 ng/ml in normoxia up to 2.1 ± 0.28 ng/ml after 16 h of hypoxia.”
Quote in the paperSubstantial claim - Findingown data
Conditioned media from hypoxic adipocytes does not significantly decrease insulin-induced phosphorylation of insulin receptor or PKB.
“In the presence of conditioned media from hypoxic adipocytes, we did not observe a significant decrease in the insulin-induced phosphorylation of the insulin receptor or PKB.”
Quote in the paperSubstantial claim - Findingown data
Echinomycin leads to partial restoration of insulin-induced tyrosine phosphorylation of insulin receptor in hypoxia.
“The use of echinomycin, an inhibitor that has been characterized to inhibit HIF activity without modulating HIF-α subunit protein levels (23), led also to partial restoration of insulin-induced tyrosine phosphorylation of the insulin receptor in hypoxia (data not shown).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Kong D, Park EJ, Stephen AG, Calvani M, Cardellina JH, Monks A, Fisher RJ, Shoemaker RH, Melillo G: Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res 65:9047–9055,2005 source
Not checked in the free run.
- Findingown data
In 3T3-L1 adipocytes, hypoxia inhibits insulin-stimulated autophosphorylation of insulin receptor.
“hypoxia inhibited the ability of insulin to stimulate the autophosphorylation of its receptor as well as the phosphorylation of PKB (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
Hypoxia does not modify IL-1β protein level in 3T3-L1 adipocytes.
“In contrast, the IL-1β protein level was not modified.”
Quote in the paperNot a substantial claim - Findingown data
ROS formation in hypoxic 3T3-L1 adipocytes is in part inhibited by N-acetyl cysteine.
“Formation of ROS was in part inhibited by the antioxidant N-acetyl cysteine.”
Quote in the paperNot a substantial claim - Findingown data
In 3T3-L1 adipocytes, hypoxia has no effect on phosphorylation of IRS-1 at Ser307 and Ser789.
“No effect of hypoxia on the phosphorylation on Ser307 and Ser789 was detected (data not shown).”
Quote in the paperNot a substantial claim - Findingown data
In 3T3-L1 adipocytes, hypoxia inhibits insulin-stimulated phosphorylation of IRS-1 at Ser632.
“Hypoxia inhibited the phosphorylation of Ser632 residue in response to insulin (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
Ectopic expression of HIF-1α or -2α in HEK-293 cells decreases insulin-stimulated insulin receptor autophosphorylation compared with control cells.
“Ectopic expression of HIF-1α or -2α subunits led to a decrease in the ability of insulin to stimulate its receptor autophosphorylation compared with control cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
siRNA against HIF-1α or -2α partly inhibits (57 ± 3%) HIF-1α and -2α expression under hypoxia.
“The siRNAs were able to partly inhibit (57 ± 3%) HIF-1α and -2α expression under hypoxia.”
Quote in the paperSubstantial claim - Findingown data
In 3T3-L1 adipocytes, hypoxia inhibits insulin-stimulated phosphorylation of PKB.
“hypoxia inhibited the ability of insulin to stimulate the autophosphorylation of its receptor as well as the phosphorylation of PKB (Fig. 1B).”
Quote in the paperSubstantial claim - Findingown data
In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by decreased phosphorylation of insulin receptor.
“In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor.”
- Also stated in: § Hypoxia inhibits the insulin signaling pathway in human adipocytes and 3T3-L1 adipocytes. · plain
“In conclusion, in both human and murine adipocytes, hypoxia inhibited the ability of insulin to induce the phosphorylation of its receptor as well as IRS-1, IRS-2, PKB, and S6K.”
Quote in the paperSubstantial claim - Also stated in: § Hypoxia inhibits the insulin signaling pathway in human adipocytes and 3T3-L1 adipocytes. · plain
- Findingown data
Total protein tyrosine phosphatase activity is not significantly different in hypoxia compared with normoxia in adipocytes.
“No significant difference in total phosphatase activity was observed in hypoxia compared with normoxia (Fig. 4B).”
Quote in the paperSubstantial claim - Interpretationreasoning
The HIF-mediated inhibition of insulin signaling could not be restricted to hypoxia because HIF proteins are induced by growth factors and cytokines.
“Because several of these circulating molecules have been shown to interact with insulin signaling, the HIF-mediated inhibition of insulin signaling described here could not be restricted to hypoxia.”
Quote in the paperNot a substantial claim - Interpretationown data
Hypoxia inhibits insulin receptor and IRS tyrosine phosphorylation through mechanisms dependent on HIF transcription factors.
“Together, these results show that hypoxia inhibited insulin receptor and IRS tyrosine phosphorylation through mechanisms that are dependent of HIF transcription factors.”
Quote in the paperSubstantial claim - Premisecitation
Obesity is associated with the formation of hypoxic areas within adipose tissue.
“Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue.”
- Also stated in: § Abstract · plain
“In addition to this proinflammatory state, obesity is associated with the formation of hypoxic areas within the tissue.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Ye J, Gao Z, Yin J, He Q: Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118–E1128,2007 source
Not checked in the free run.
- cites [3] Rausch ME, Weisberg S, Vardhana P, Tortoriello DV: Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T-cell infiltration. Int J Obes (Lond) 32:451–463,2008 source
Not checked in the free run.
- cites [4] Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I: Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56:901–911,2007 source
Not checked in the free run.
- Also stated in: § Abstract · plain
- Interpretationreasoning
Hypoxia could be a new mechanism that participates in insulin resistance in adipose tissue of obese patients.
“Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro effects of hypoxia on adipocytes reflect the in vivo situation in adipose tissue of obese patients.
- Interpretationown data
Hypoxia-induced insulin resistance is rapidly reversible.
“Indeed, hypoxia-induced insulin resistance is rapidly reversible.”
Quote in the paperSubstantial claim - Interpretationown data
The inhibition of insulin signaling by hypoxia is dependent upon HIF-1 and -2 transcription factors.
“Using experiments of gain and loss of function, we have shown that the inhibition of insulin signaling by hypoxia is dependent upon HIF-1 and -2 transcription factors.”
Quote in the paperSubstantial claim - Interpretationown data
Hypoxia-induced cytokine production by adipocytes is not the mechanism responsible for the inhibition of insulin signaling by hypoxia.
“This suggests that hypoxia-induced cytokine production by adipocytes is not the mechanism responsible for the inhibition of insulin signaling that we describe here.”
Quote in the paperSubstantial claim- Rests on an assumption: During hypoxia and obesity, cytokines are mainly produced by macrophages that invade adipose tissue and not by adipocytes per se.
- Study design and conductown data
Hypoxia does not induce cell toxicity in 3T3-L1 adipocytes, as measured by lactate dehydrogenase activity or caspase 3 activity.
“It is to be noted that hypoxia did not induce cell toxicity, as measured by lactate deshydrogenase activity, or caspase 3 activity (data not shown).”
Quote in the paperNot a substantial claim - Interpretationown data
Hypoxia does not mediate its inhibition of insulin signaling through activation of tyrosine phosphatase activities.
“These results suggest that hypoxia did not mediate its action through the activation of tyrosine phosphatase activities.”
Quote in the paperSubstantial claim - Premisecitation
Hypoxia in adipose tissue of obese patients is supported by the observation that cardiac output and blood flow directed to adipose tissue are not increased during obesity.
“In humans, the existence of hypoxia in the adipose tissue of obese patients is supported by the observation that although obese patients have more adipose tissue than lean patients, the cardiac output and blood flow directed to adipose tissue are not increased during obesity (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Trayhurn P, Wang B, Wood IS: Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity?Br J Nutr 100:227–235,2008 source
Not checked in the free run.
- May combine two claims. 11
- Classified as probably not a substantial claim. 1
May combine two claims.
Findingown dataHypoxia impairs insulin-stimulated phosphorylation of insulin receptor, PKB, and AS160, and reoxygenation restores this phosphorylation after 45 min.
“Hypoxia impaired the ability of insulin to stimulate insulin receptor tyrosine phosphorylation as well as PKB and AS160 phosphorylation. During reoxygenation, the ability of insulin to stimulate phosphorylation of insulin receptor and signaling proteins was restored after 45 min.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataReoxygenation of 3T3-L1 adipocytes restores insulin-stimulated glucose entry to levels comparable to normoxic adipocytes, while basal glucose transport remains elevated.
“Reoxygenation of adipocytes restored the ability of insulin to stimulate glucose entry to levels comparable to normoxic adipocytes. In reoxygenated adipocytes, basal glucose transport remained elevated.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataHypoxia stimulates ROS generation in 3T3-L1 adipocytes as soon as 1 h, maintained up to 16 h.
“Hypoxia stimulated the generation of ROS as soon as 1 h, which was maintained up to 16 h (Fig. 4A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCoCl2 decreases insulin-stimulated insulin receptor and IRS tyrosine phosphorylation without affecting their protein levels.
“Concomitantly, CoCl2 decreased the ability of insulin to stimulate insulin receptor and IRS tyrosine phosphorylation without affecting their respective protein levels.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn 3T3-L1 adipocytes, hypoxia upregulates basal glucose transport but inhibits insulin-induced glucose transport.
“Hypoxia upregulated basal glucose transport but inhibited insulin-induced glucose transport.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe inhibitory effect of hypoxia on insulin receptor tyrosine phosphorylation is detected as soon as 1 h and is more pronounced after 8 h.
“the inhibitory effect of hypoxia on insulin receptor tyrosine phosphorylation was detected as soon as 1 h. These effects were more pronounced after 8 h of hypoxia.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBecause hypoxia affects the earliest intracellular step of insulin signaling, i.e., insulin receptor autophosphorylation, all subsequent steps, such as IRS and PKB phosphorylation and glucose transport, were affected.
“Because hypoxia affects the earliest intracellular step of insulin signaling, i.e., insulin receptor autophosphorylation, all subsequent steps, such as IRS and PKB phosphorylation and glucose transport, were affected.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataHypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression.
“We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe increase in basal glucose uptake after reoxygenation probably results from increased GLUT1 expression, which is maintained after 1 h of reoxygenation, without modification of GLUT4 protein levels.
“This increase in basal glucose uptake probably resulted from increased GLUT1 expression, which was maintained even after 1 h of reoxygenation, without modifying GLUT4 protein levels (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationUnder hypoxia, energy expenditure is decreased, leading to inhibition of high-energy-consuming events such as protein translation, leading to inhibition of mTOR and S6K.
“Under hypoxia, energy expenditure is decreased, leading to the inhibition of high–energy-consuming events such as protein translation, leading to the inhibition of mTOR and S6K (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr: Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904,2004 source
Not checked in the free run.
May combine two claims.
PremisecitationHIF-1 and HIF-1 target genes are overexpressed in adipose tissue of obese individuals and decrease after weight loss.
“Moreover, HIF-1 and HIF-1 target genes are overexpressed in the adipose tissue of obese individuals and decrease after weight loss (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Cancello R, Henegar C, Viguerie N, Taleb S, Poitou C, Rouault C, Coupaye M, Pelloux V, Hugol D, Bouillot JL, Bouloumie A, Barbatelli G, Cinti S, Svensson PA, Barsh GS, Zucker JD, Basdevant A, Langin D, Clement K: Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes 54:2277–2286,2005 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIRS-1 Ser632 is a target for mTOR and S6K.
“Hypoxia decreased IRS-1 serine phosphorylation on Ser632 residue, which is a target for mammalian target of rapamycin (mTOR) and S6K (19).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [19] Gual P, Le Marchand-Brustel Y, Tanti JF: Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87:99–109,2005 source
Not checked in the free run.
The paper relies on this without support.
During hypoxia and obesity, cytokines are mainly produced by macrophages that invade adipose tissue and not by adipocytes per se.
“This is consistent with the observation that during hypoxia and obesity, cytokines are mainly produced by macrophages that invade the adipose tissue and not by adipocytes per se.”
The paper relies on this without support.
Obesity is associated with hypertrophic adipocytes in which size prohibits correct diffusion of O2 within the tissue.
“Finally, obesity is associated with hypertrophic adipocytes in which size prohibits a correct diffusion of O2 within the tissue.”
The paper relies on this without support.
The in vitro effects of hypoxia on adipocytes reflect the in vivo situation in adipose tissue of obese patients.
“Our in vitro system allowed us to show the direct effect of hypoxia on adipocytes.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Hypoxia per se decreases insulin signaling and disrupts lipid metabolism in AT.
“Hypoxia per se decreases insulin signaling and disrupts lipid metabolism in AT”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Regazzetti et al., 2009
The Results (page unavailable) show that hypoxia directly inhibits insulin signaling in cultured human and murine adipocytes and stimulates glycerol release, a measure of lipolysis, in 3T3-L1 adipocytes. The claim extends those findings to disrupted lipid metabolism in adipose tissue (AT) generally; the paper reports a specific lipid-related effect in cultured adipocytes, not a general tissue-level finding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn insulin-responsive tissues, sustained HIF-1 activation promotes a shift toward glycolytic metabolism, alters mitochondrial function, and contributes to insulin resistance by disrupting normal oxidative metabolism and redox balance.
“In insulin responsive tissues, sustained HIF-1 activation promotes a shift toward glycolytic metabolism, alters mitochondrial function, and contributes to insulin resistance by disrupting normal oxidative metabolism and redox balance [236,237].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [237]
The Discussion (page unavailable) reports that hypoxia inhibits insulin signaling in rodent adipocytes through HIF-1 and HIF-2. The paper also describes a hypoxia-associated shift toward glycolysis and reports increased reactive oxygen species, but it does not show that sustained HIF-1 activation alters mitochondrial function or causes insulin resistance by disrupting oxidative metabolism and redox balance across insulin-responsive tissues. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The citation lists haven’t been fetched yet
References 34 · Cited by 281
- Authors
- Regazzetti, C., Peraldi, P., Grémeaux, T., Najem-Lendom, R., Ben-Sahra, I., Cormont, M., Bost, F., Le Marchand-Brustel, Y., Tanti, J.-F., & Giorgetti-Peraldi, S.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Team: Cellular and Molecular Physiopathology of Obesity and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) U 895, Mediterranean Research Centre for Molecular Medicine, Nice, France
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2009-01-01
- Volume
- 58
- Issue
- 1
- Pages
- 95-103
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2606898
- OpenAlex
- W2100503932
- Semantic Scholar
- 72e6fd66e66adf195bd5c5a7ef37d53d31012997
- Cited by
- 281
- References
- 34
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 8 · 2023: 9 · 2022: 12 · 2021: 20 · 2020: 15 · 2019: 22 · 2018: 15 · 2017: 10 · 2016: 16 · 2015: 23 · 2014: 24 · 2013: 22 · 2012: 19
- FWCI
- 11.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- European Commission (LSHM‐CT‐2005‐018734)
- Université Nice Sophia Antipolis
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- hypoxia, insulin resistance, adipocytes, insulin signaling, hypoxia-inducible factor, HIF-1α, HIF-2α, insulin receptor phosphorylation, Akt, AS160, glucose transport, obesity, adipose tissue
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Biological Transport, Cell Line, Cobalt, Glucose, Glycerol, Humans, Hypoglycemic Agents, Insulin, Lipolysis, Phosphorylation, Receptor, Insulin, Blotting, Western, Signal Transduction, Cell Hypoxia, Interleukin-6, Protein Tyrosine Phosphatases, Reactive Oxygen Species, Adipocytes, 3T3-L1 Cells, Mice, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-1beta
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