Thermoneutrality modifies the impact of hypoxia on lipid metabolism

Abstract

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.

Intermittent hypoxia-induced glucose intolerance is abolished by α-adrenergic blockade or adrenal medullectomy

“…3). We (41) and others have demonstrated that hypoxia can stimulate or suppress lipolysis depending on experimental conditions (6,7,43,66). Perhaps ODI 60 induces a lipolytic SNS response without elevating lactate, which can inhibit lipolysis (25).…”

“…In small mammals, cool ambient temperatures significantly raise the metabolic rate (15,50), and hypoxia suppresses this reflex (31). Hence, interactions of cold and hypoxia can obscure the effects of hypoxia itself (41). Third, most studies involve IH exposures lasting days to weeks in an effort to simulate the chronic IH of OSA.…”

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…Adaptive thermogenesis, also known as non-shivering thermogenesis, is a mechanism of metabolic heat production which involves stimulation of the Trends Several mouse models show significant differences in experimental outcomes at standard sub-thermoneutral (ST, 22-26 8C) versus thermoneutral housing temperatures (TT,(30)(31)(32), including models of cardiovascular disease, obesity, inflammation and atherosclerosis, graft versus host disease and cancer.…”

“…However, these measures are not always in place, and even when they are, mice are often seen to 'huddle' to minimize heat loss and exhibit signs of cold stress [6]. Researchers have noted a variety of significant differences in mice housed at ST versus TT, including differences in basal metabolism [12], cardiovascular physiology [27,28], the size of organs and tail length [29], and the effects of hypoxia on lipolysis during thermogenesis [30]. Physiological responses such as heart rate and metabolic rate have a linear relationship with the ambient temperature (see review by Maloney et al [22]).…”

Metabolic dysfunction in obstructive sleep apnea: A critical examination of underlying mechanisms

“…178 Therefore, hypoxia at relatively cool ambient temperatures can lead to a dramatic fall in metabolic rate, deceleration of tissue lipid uptake, and the development of hyperlipidemia 179 – a finding not seen at warmer ambient temperature. 180 Besides eliciting these systemic responses, hypoxia also can directly affect cellular metabolism at the tissue level. For the purposes of this review, we will focus on tissue-level hypoxia, since this is a commonly cited hypothesis connecting OSA to metabolic dysfunction.…”