Abstract
Blood glucose and the prevalence of diabetes are lower in mountain than lowland dwellers, which could among other factors be due to reduced oxygen availability. To investigate metabolic adaptations to life under hypoxia, male mice on high fat diet (HFD) were continuously maintained at 10% O2. At variance to preceding studies, the protocol was designed to dissect direct metabolic effects from such mediated indirectly via hypoxia-induced reductions in appetite and weight gain. This was achieved by two separate control groups on normal air, one with free access to HFD, and one fed restrictedly in order to obtain a weight curve matching that of hypoxia-exposed mice. Comparable body weight in restrictedly fed and hypoxic mice was achieved by similar reductions in calorie intake (−22%) and was associated with parallel effects on body composition as well as on circulating insulin, leptin, FGF-21, and adiponectin. Whereas the effects of hypoxia on the above parameters could thus be attributed entirely to blunted weight gain, hypoxia improved glucose homeostasis in part independently of body weight (fasted blood glucose, mmol/l: freely fed control, 10.2 ± 0.7; weight-matched control, 8.0 ± 0.3; hypoxia, 6.8 ± 0.2; p < 0.007 each; AUC in the glucose tolerance test, mol/l*min: freely fed control, 2.54 ± 0.15; weight-matched control, 1.86 ± 0.08; hypoxia, 1.67 ± 0.05; p < 0.05 each). Although counterintuitive to lowering of glycemia, insulin sensitivity appeared to be impaired in animals adapted to hypoxia: In the insulin tolerance test, hypoxia-treated mice started off with lower glycaemia than their weight-matched controls (initial blood glucose, mmol/l: freely fed control, 11.5 ± 0.7; weight-matched control, 9.4 ± 0.3; hypoxia, 8.1 ± 0.2; p < 0.02 each), but showed a weaker response to insulin (final blood glucose, mmol/l: freely fed control, 7.0 ± 0.3; weight-matched control, 4.5 ± 0.2; hypoxia, 5.5 ± 0.3; p < 0.01 each). Furthermore, hypoxia weight-independently reduced hepatic steatosis as normalized to total body fat, suggesting a shift in the relative distribution of triglycerides from liver to fat (mg/g liver triglycerides per g total fat mass: freely fed control, 10.3 ± 0.6; weight-matched control, 5.6 ± 0.3; hypoxia, 4.0 ± 0.2; p < 0.0004 each). The results show that exposure of HFD-fed mice to continuous hypoxia leads to a unique metabolic phenotype characterized by improved glucose homeostasis along with evidence for impaired rather than enhanced insulin sensitivity.
Highlights
Basal blood glucose and insulin resistance, as well as the prevalence of obesity and diabetes have been shown to be lower in mountain than lowland dwellers, which among many other factors could be due to the lower partial oxygen pressure at high altitude [1,2,3,4,5]
The amount of high fat diet (HFD), to which mice at normal air had to be restricted in order to obtain a similar weight curve as in those living under hypoxia, was almost the same as what the hypoxia exposed mice consumed deliberately (HFD restricted vs. HFD+hypoxia; Figures 2A,B)
Plasma adiponectin showed a minor increase in association with HFD induced obesity, which is at variance to most, but not all reports from the literature [e.g. [33,34,35,36]], and which was reversed with amelioration of obesity by hypoxia or restricted feeding (Figure 3C)
Summary
Basal blood glucose and insulin resistance, as well as the prevalence of obesity and diabetes have been shown to be lower in mountain than lowland dwellers, which among many other factors could be due to the lower partial oxygen pressure at high altitude [1,2,3,4,5]. Some rodent experiments were designed to mimic the episodes of recurrent short-term oxygen deficiency as typically occurring in obstructive sleep apnea. The majority of such studies, in which rodents were exposed to rapidly alternating cycles of hypoxia and normoxia, found detrimental effects on glucose tolerance, insulin sensitivity and hepatic steatosis [6,7,8,9,10]. While the metabolic derangements seen with intermittent hypoxia or with short term continuous hypoxia could in part be due to a stress response associated with adrenergic signaling and/or a rise in plasma corticosteroids [14, 16, 17, 19,20,21,22], the majority of studies in humans and animals suggested a turn toward normal or even improved glucose homeostasis with prolonged life under continuous low oxygen availability [3, 11, 13, 16, 18, 19, 23, 24]
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