Thermoneutrality modifies the impact of hypoxia on lipid metabolism

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.