Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period

Am J Physiol Regul Integr Comp Physiol. 2012 Oct 1;303(7):R700-9. doi: 10.1152/ajpregu.00258.2012. Epub 2012 Aug 15.


Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IH(L)) have not been extensively examined, it would appear that IH(L) and high-frequency intermittent hypoxia (IH(H)) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IH(H) (cycles of 90 s 6.4% O(2) and 90 s 21% O(2) during daylight), IH(L) (8% O(2) during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IH(H) and IH(L) displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IH(L) and IH(H), with IH(L) manifesting the lowest insulin sensitivity compared with either IH(H) or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IH(L), IH(H), and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IH(L)-exposed mice. Thus IH(H) and IH(L) elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptation, Physiological / physiology*
  • Animals
  • Body Weight / physiology
  • Circadian Rhythm / physiology*
  • Glucose Transporter Type 4 / metabolism
  • Hypoxia / metabolism*
  • Insulin / blood
  • Leptin / blood
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Muscle, Skeletal / metabolism
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Rest / physiology*
  • Time Factors
  • Trans-Activators / metabolism
  • Transcription Factors


  • Glucose Transporter Type 4
  • Insulin
  • Leptin
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Slc2a4 protein, mouse
  • Trans-Activators
  • Transcription Factors