Hypoxia stimulates lactate release and modulates monocarboxylate transporter (MCT1, MCT2, and MCT4) expression in human adipocytes
ABSTRACT Hypoxia modulates white adipose tissue function, and this includes stimulating glucose uptake and the expression of facilitative glucose transporters (particularly GLUT1) in adipocytes. This study has examined the effect of hypoxia on lactate release from adipocytes and whether the monocarboxylate transporters that mediate lactate transport (MCTs1-4) are expressed in human adipocytes and are induced by low O(2) tension. Exposure of human Simpson-Golabi-Behmel syndrome adipocytes to 1% O(2) for 24 h resulted in increased lactate release (2.3-fold) compared with cells in normoxia (21% O(2)). Screening by reverse transcription polymerase chain reaction indicated that the genes encoding MCT1, MCT2, and MCT4 are expressed in human adipose tissue, and in adipocytes and preadipocytes in culture. Hypoxia (48 h) increased MCT1 (8.5-fold) and MCT4 (14.3-fold) messenger RNA (mRNA) levels in human adipocytes, but decreased MCT2 mRNA (fourfold). MCT1 protein level was also increased (2.7-fold at 48 h) by hypoxia, but there was no change in MCT4 protein. The changes in MCT gene expression induced by hypoxia were reversed on return to normoxia. Treatment with the hypoxia mimetic CoCl(2) resulted in up-regulation of MCT1 (up to twofold) and MCT4 (fivefold) mRNA level, but there was no significant effect on MCT2 expression. It is concluded that hypoxia increases lactate release from adipocytes and modulates MCT expression in a type-specific manner, with MCT1 and MCT4 expression being hypoxia-inducible transcription factor-1 (HIF-1) dependent. Increased lactate production and monocarboxylate transporter expression are likely to be key components of the adaptive response of adipocytes to low O(2) tension as adipose tissue mass expands in obesity.
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ABSTRACT: Obesity, a multi-factorial disease caused by excessive accumulation of fat in adipose tissue causing impairment of routine health. It is measured in term of body mass index (BMI) and the person having more than 30 BMI is generally considered as obese. Its prevalence has been increased with alarming speed over the past twenty years and recently World Health Organization (WHO) recognises it as a 'global epidemic'. Various etiological factors are concerned with pathogenesis of obesity like energy business, serum level of iron, inflammation to adipose tissue, hypoxia etc. Shilajeet, an Ayurvedic medicines is exudates come out from rock during hot sunny days and contains mainly fulvic, humic acid along with higher percentage of iron. It is indicated for management of varieties of disorders like obesity, diabetes etc. as a single medicine or in combination with other herbs, metal and mineral. Shilajeet enhances energy business by improving activity of nicotinamide adenine dinucleotide (NADH) dehydrogenases, succinate dehydrogenase (SDH) and cytochrome oxidase, enhances serum iron concentration and facilitates oxygenation to tissues by increasing oxygen carrying capacity with facilitation of blood circulation to tissue. In this review paper it is being established that all these characters of Shilajeet may be probable reason for its effect on management of obesity.
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ABSTRACT: Relative hypoxia has been shown to develop in white adipose tissue depots of different types of obese mouse (genetic, dietary), and this leads to substantial changes in white adipocyte function. These changes include increased production of inflammation-related adipokines (such as IL-6, leptin, Angptl4, and VEGF), an increase in glucose utilization and lactate production, and the induction of fibrosis and insulin resistance. Whether hypoxia also occurs in brown adipose tissue depots in obesity has been little considered. However, a recent study has reported low pO2 in brown fat of obese mice, this involving mitochondrial loss and dysfunction. We suggest that obesity-linked hypoxia may lead to similar alterations in brown adipocytes as in white fat cells - particularly changes in adipokine production, increased glucose uptake and lactate release, and insulin resistance. This would be expected to compromise thermogenic activity and the role of brown fat in glucose homeostasis and triglyceride clearance, underpinning the development of the metabolic syndrome. Hypoxia-induced augmentation of lactate production may also stimulate the "browning" of white fat depots through recruitment of UCP1 and the development of brite adipocytes.Frontiers in Endocrinology 02/2015; 6:19. DOI:10.3389/fendo.2015.00019
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ABSTRACT: Neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO) were previously demonstrated in transient and permanent ischemic stroke. Here we sought to identify whether enhanced lactic acidosis and reduced monocarboxylate transporters (MCTs) after stroke might be attenuated by single or combined EtOH and NBO therapies. Sprague-Dawley rats (n=96) were subjected to right middle cerebral artery occlusion (MCAO) for 2 or 4h (transient ischemia), or 28h (permanent ischemia) followed by 3, 24h, or no reperfusion. Rats received: 1) either an intraperitoneal injection of saline (sham treatment), one dose of EtOH (1.5g/kg), two doses of EtOH (1.5g/kg at 2h of MCAO, followed by 1.0g/kg 2h after 1st dose), or 2) EtOH+95% NBO (at 2h of MCAO for 6h in permanent ischemia). Lactate levels were detected at 3 and 24h of reperfusion. Gene and protein expressions of MCT-1,-2, -4 were assessed by real time-PCR and Western Blotting. A dose-dependent EtOH neuroprotection was found in transient ischemia. Following transient ischemia, a single dose of EtOH (in 2h-MCAO) or a double dose (in 4h-MCAO), significantly attenuated lactate levels, as well as the mRNAs and protein expressions of MCT-1, MCT-2, and MCT-4. However while two doses of EtOH alone was ineffective in permanent stroke, the combined therapy (EtOH+95% NBO) resulted in a more significant attenuation in all the above levels and expressions. Our study demonstrates that acute EtOH administration attenuated lactic acidosis in transient or permanent ischemic stroke. This EtOH-induced beneficial effect was potentiated by NBO therapy in permanent ischemia. Because both EtOH and NBO are readily available, inexpensive and easy to administer, their combination could be implemented in the clinics shortly after stroke. Copyright © 2015. Published by Elsevier B.V.Brain Research 01/2015; 1603. DOI:10.1016/j.brainres.2015.01.040 · 2.83 Impact Factor