Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

Muñoz, Sergio; Franckhauser, Sylvie; Elias, Ivet; Ferré, Tura; Hidalgo, Antonio; Monteys, Alex Mas; Molas, Maria; Cerdán, Sebastián; Pujol, Anna; Ruberte, Jesús; Bosch, Fátima

doi:10.1007/s00125-010-1840-7

Cited by 39 publications

(33 citation statements)

References 47 publications

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“…From the data presented we can postulate an additional role for adipocytes in energy homoeostatic regulation: WAT helps decrease plasma glucose, especially under hyperglycemia, and thus indirectly improving insulin resistance39. As indicated above, WAT is the last dumping site for glucose under insulin resistance-induced hyperglycemia2740.…”

Section: Discussionmentioning

confidence: 68%

Cultured 3T3L1 adipocytes dispose of excess medium glucose as lactate under abundant oxygen availability

Sabater

Arriarán

Romero

et al. 2014

Sci Rep

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White adipose tissue (WAT) produces lactate in significant amount from circulating glucose, especially in obesity;Under normoxia, 3T3L1 cells secrete large quantities of lactate to the medium, again at the expense of glucose and proportionally to its levels. Most of the glucose was converted to lactate with only part of it being used to synthesize fat. Cultured adipocytes were largely anaerobic, but this was not a Warburg-like process. It is speculated that the massive production of lactate, is a process of defense of the adipocyte, used to dispose of excess glucose. This way, the adipocyte exports glucose carbon (and reduces the problem of excess substrate availability) to the liver, but the process may be also a mechanism of short-term control of hyperglycemia. The in vivo data obtained from adipose tissue of male rats agree with this interpretation.

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Section: Discussionmentioning

confidence: 68%

Cultured 3T3L1 adipocytes dispose of excess medium glucose as lactate under abundant oxygen availability

Sabater

Arriarán

Romero

et al. 2014

Sci Rep

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“…For example, specific ablation of glucose transporter 4 (GLUT4) in adipocytes significantly impairs skeletal muscle insulin sensitivity in mice (2,35). Likewise, chronic increases in adipocyte glucose uptake improve whole body insulin sensitivity (36–38). Thus, it is possible that the ~50% increase in glucose uptake observed in nitrite-treated adipocytes in this study represents a mechanism underlying the nitrite-dependent beneficial regulation of glucose homeostasis in metabolic syndrome previously described.…”

Section: Discussionmentioning

confidence: 99%

Nitrite augments glucose uptake in adipocytes through the protein kinase A-dependent stimulation of mitochondrial fusion

Khoo

Zharikov

et al. 2014

Free Radical Biology and Medicine

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Though it is well accepted that adipose tissue is central in the regulation of glycemic homeostasis, the molecular mechanisms governing adipocyte glucose uptake remain unclear. Recent studies demonstrate that mitochondrial dynamics (fission and fusion) regulate lipid accumulation and differentiation in adipocytes. However, the role of mitochondrial dynamics in glucose homeostasis has not been explored. The nitric oxide oxidation products nitrite and nitrate are endogenous signaling molecules and dietary constituents that have recently been shown to modulate glucose metabolism, prevent weight gain and reverse the development of metabolic syndrome in mice. While the mechanism of this protection is unclear, the mitochondrion is a known subcellular target for nitrite signaling. Thus, we hypothesize that nitrite modulates mitochondrial dynamics and function to regulate glucose uptake in adipocytes. Herein, we demonstrate that nitrite significantly increases glucose uptake in differentiated murine adipocytes through a mechanism dependent on mitochondrial fusion. Specifically, nitrite promotes mitochondrial fusion by increasing pro-fusion protein mitofusin 1 while concomitantly activating protein kinase A (PKA), which phosphorylates and inhibits the pro-fission protein, dynamin-related protein 1 (Drp1). Functionally, this signaling augments cellular respiration, fatty acid oxidation, mitochondrial oxidant production and glucose uptake. Importantly, inhibition of PKA or Drp1 significantly attenuates nitrite-induced mitochondrial respiration and glucose uptake. These findings demonstrate that mitochondria play an essential metabolic role in adipocytes, a novel role for both nitrite and mitochondrial fusion in regulating adipocyte glucose homeostasis and have implications for the potential therapeutic use of nitrite and mitochondrial modulators in glycemic regulation.

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“…Adipocytes area was determined as previously described (21). Four animals per group were used and at least 250 adipocytes per animal were analyzed.…”

Section: Methodsmentioning

confidence: 99%

Adipose Tissue Overexpression of Vascular Endothelial Growth Factor Protects Against Diet-Induced Obesity and Insulin Resistance

et al. 2012

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During the expansion of fat mass in obesity, vascularization of adipose tissue is insufficient to maintain tissue normoxia. Local hypoxia develops and may result in altered adipokine expression, proinflammatory macrophage recruitment, and insulin resistance. We investigated whether an increase in adipose tissue angiogenesis could protect against obesity-induced hypoxia and, consequently, insulin resistance. Transgenic mice overexpressing vascular endothelial growth factor (VEGF) in brown adipose tissue (BAT) and white adipose tissue (WAT) were generated. Vessel formation, metabolism, and inflammation were studied in VEGF transgenic mice and wild-type littermates fed chow or a high-fat diet. Overexpression of VEGF resulted in increased blood vessel number and size in both WAT and BAT and protection against high-fat diet–induced hypoxia and obesity, with no differences in food intake. This was associated with increased thermogenesis and energy expenditure. Moreover, whole-body insulin sensitivity and glucose tolerance were improved. Transgenic mice presented increased macrophage infiltration, with a higher number of M2 anti-inflammatory and fewer M1 proinflammatory macrophages than wild-type littermates, thus maintaining an anti-inflammatory milieu that could avoid insulin resistance. These studies suggest that overexpression of VEGF in adipose tissue is a potential therapeutic strategy for the prevention of obesity and insulin resistance.

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Chronically increased glucose uptake by adipose tissue leads to lactate production and improved insulin sensitivity rather than obesity in the mouse

Cited by 39 publications

References 47 publications

Cultured 3T3L1 adipocytes dispose of excess medium glucose as lactate under abundant oxygen availability

Cultured 3T3L1 adipocytes dispose of excess medium glucose as lactate under abundant oxygen availability

Nitrite augments glucose uptake in adipocytes through the protein kinase A-dependent stimulation of mitochondrial fusion

Adipose Tissue Overexpression of Vascular Endothelial Growth Factor Protects Against Diet-Induced Obesity and Insulin Resistance

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