Hypertriglyceridemia in rats at simulated high altitudes

Louhija, Antti

doi:10.1007/bf02034371

Cited by 10 publications

(7 citation statements)

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“…Fourth, hypoxia was induced by increasing ambient nitrogen concentration. Similar findings with regard to TG levels been reported for hypobaric or altitude hypoxia (10,14,43,71), demonstrating equivalent effects of lowering oxygen saturation by either means.…”

Section: Discussionsupporting

confidence: 84%

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Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

Jun

Shin

Yao

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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(TG). We previously demonstrated that mice exposed to chronic IH develop elevated TG. We now hypothesize that a single exposure to acute hypoxia also increases TG due to the stimulation of free fatty acid (FFA) mobilization from white adipose tissue (WAT), resulting in increased hepatic TG synthesis and secretion. Male C57BL6/J mice were exposed to FiO2 ϭ 0.21, 0.17, 0.14, 0.10, or 0.07 for 6 h followed by assessment of plasma and liver TG, glucose, FFA, ketones, glycerol, and catecholamines. Hypoxia dosedependently increased plasma TG, with levels peaking at FiO2 ϭ 0.07. Hepatic TG levels also increased with hypoxia, peaking at FiO2 ϭ 0.10. Plasma catecholamines also increased inversely with FiO2. Plasma ketones, glycerol, and FFA levels were more variable, with different degrees of hypoxia inducing WAT lipolysis and ketosis. FiO2 ϭ 0.10 exposure stimulated WAT lipolysis but decreased the rate of hepatic TG secretion. This degree of hypoxia rapidly and reversibly delayed TG clearance while decreasing [ 3 H]triolein-labeled Intralipid uptake in brown adipose tissue and WAT. Hypoxia decreased adipose tissue lipoprotein lipase (LPL) activity in brown adipose tissue and WAT. In addition, hypoxia decreased the transcription of LPL, peroxisome proliferator-activated receptor-␥, and fatty acid transporter CD36. We conclude that acute hypoxia increases plasma TG due to decreased tissue uptake, not increased hepatic TG secretion.lipolysis; lipases; adipose; thermoregulation; metabolism OBSTRUCTIVE SLEEP APNEA (OSA) causes recurrent episodes of asphyxia and intermittent hypoxia (IH) during sleep. Several studies reveal an association between OSA and elevated circulating triglycerides (TG) (16). In some cases, the severity of hypoxia during sleep correlates with the magnitude of increased TG (18, 48). Furthermore, therapy for OSA with continuous positive airway pressure (CPAP) decreases fasting (61) and postprandial TG levels (51); yet, the mechanisms by which OSA affects TG levels are unclear. One possibility is that repetitive IH increases TG levels. Our laboratory has simulated hypoxic desaturations of OSA in mice, exposing them to diurnal IH (60 desaturations/h, 12 h/day). After chronic IH exposure, mice exhibited ϳ40% increases in plasma TG after 5 days (40), with similar elevations persisting after 4 and 12 wk of ongoing IH exposure (32). We have also shown that chronic IH increases TG via two major mechanisms, increased hepatic secretion (39) and decreased lipoprotein clearance (17).Two important questions have not been addressed by chronic IH experiments. First, is chronicity of hypoxia necessary to affect lipid metabolism? Second, is intermittency a necessary factor? Short-term sustained hypoxia in humans (2, 19, 71) and animals (43, 47) also induces hypertriglyceridemia. Surprisingly, no studies have systematically examined the mechanisms by which acute hypoxic exposures elevate TG. It is conceivable that acute sustained hypoxia increases TG via the same mechanisms that we have described for chronic IH. We ther...

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Section: Discussionsupporting

confidence: 84%

“…Second, is intermittency a necessary factor? Short-term sustained hypoxia in humans (2,19,71) and animals (43,47) also induces hypertriglyceridemia. Surprisingly, no studies have systematically examined the mechanisms by which acute hypoxic exposures elevate TG.…”

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confidence: 99%

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

Jun

Shin

Yao

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…First, weight loss under hypoxic conditions may have detrimental consequences. High-altitude dwellers, chronic commuters between high and low altitudes (Siques et al 2007), and rats exposed to hypobaric hypoxia (Louhija 1969) have elevated triglyceride levels. This observation has not been fully explained, but would be a logical consequence of elevated circulating and hepatic free fatty acids liberated from fat stores during hypoxia.…”

Section: Effects Of Intermittent Hypoxia: Evidence From Animal Modelsmentioning

confidence: 99%

Metabolic Consequences of Sleep-Disordered Breathing

Jun¹,

Polotsky²

2009

ILAR Journal

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There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.

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“…To date, the potential mechanisms by which hypoxia increases plasma lipids have not been studied in humans. However, rodents exposed to various forms of acute hypoxia (42,46) develop hyperlipidemia, allowing for translational mechanistic studies. In mice, we showed recently that TG increase within 6 h of hypoxic exposure and that the magnitude of TG elevation correlated directly with the severity of hypoxia (36).…”

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confidence: 99%

Thermoneutrality modifies the impact of hypoxia on lipid metabolism

Jun

Shin

Yao

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Hypoxia has been shown to rapidly increase triglycerides in mice by decreasing plasma lipoprotein clearance. However, the usual temperature of hypoxic exposure is below thermoneutrality for mice, which may increase thermogenesis and energy requirements, resulting in higher tissue lipid uptake. We hypothesize that decreased lipid clearance and ensuing hyperlipidemia are caused by hypoxic suppression of metabolism at cold temperatures and, therefore, would not occur at thermoneutrality. Twelve-week-old, male C57BL6/J mice were exposed to 6 h of 10% O₂ at the usual temperature (22°C) or thermoneutrality (30°C). Acclimation to 22°C increased lipid uptake in the heart, lungs, and brown adipose tissue, resulting in lower plasma triglyceride and cholesterol levels. At this temperature, hypoxia attenuated lipid uptake in most tissues, thereby raising plasma triglycerides and LDL cholesterol. Thermoneutrality decreased tissue lipid uptake, and hypoxia did not cause a further reduction in lipid uptake in any organs. Consequently, hypoxia at thermoneutrality did not affect plasma triglyceride levels. Unexpectedly, plasma HDL cholesterol increased. The effect of hypoxia on white adipose tissue lipolysis was also modified by temperature. Independent of temperature, hypoxia increased heart rate and glucose and decreased activity, body temperature, and glucose sensitivity. Our study underscores the importance of ambient temperature for hypoxia research, especially in studies of lipid metabolism.

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Hypertriglyceridemia in rats at simulated high altitudes

Cited by 10 publications

References 0 publications

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

Metabolic Consequences of Sleep-Disordered Breathing

Thermoneutrality modifies the impact of hypoxia on lipid metabolism

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