Adaptation to hypoxia: a template to fight metabolic disease

For an increasing number of humans, economic prosperity permits almost free access to calorie-rich food with little need for physical activity. Modern lifestyle goes along with a steep increase in the prevalence of obesity and associated metabolic derangements, which includes epidemic rises in type 2 diabetes and non-alcoholic fatty liver disease (overshooting accumulation of fat in the liver). In the face of this major societal and medical challenge, it is essential to forward our knowledge of how the body regulates blood glucose and hepatic fat content, and to develop novel strategies for effective therapeutic intervention. In this context, it has been noted that the mentioned disorders are less prevalent in mountain dwellers, which may, at least in part, be due to reduced oxygen availability (hypoxia) at high altitude. Studies in humans and experimental rodents have indeed indicated that prolonged residence in a hypoxic environment could have beneficial effects on metabolic traits. Hypoxia is also known to reduce appetite and body weight, but it has never been dissected, whether the hypoxia-induced improvement of metabolism is more than the simple consequence of a leaner state. To sort this out, we have exposed obese mice for several months to hypoxia, mimicking a stay at approximately 5.500 m above sea level. By controlling their access to food we avoided differences between the hypoxia-treated and the control mice with regard to calorie intake, body weight or fat mass. Although our protocol excluded indirect effects via different body weight, hypoxia still reduced blood glucose by more than 20% and liver fat by more than 40%. Further preliminary results suggested that these benefits cannot be explained by mechanisms known to cause similar metabolic improvement in response to other interventions like, e.g., drug treatment or regular physical activity. This strongly suggests the involvement of novel, previously undiscovered mechanisms. Using a standardised protocol for the exposure of mice and rats to hypoxia as well as modern techniques for the measurement of metabolic parameters, the project aims to understand, in what manner the body adapts to hypoxia to accomplish metabolic improvement. Several experiments have been designed to sort out, in what way the brain and/or hormones mediate the beneficial effects of hypoxia and which molecular processes inside the brain and/or peripheral organs like liver and muscle are responsible. The proposed study holds a unique chance to find and understand previously undiscovered mechanisms, via which the body can counteract obesity-associated metabolic derangements. This novel knowledge can then be exploited for the development of novel strategies to prevent and to treat common metabolic disorders in humans.

It has been reported that a prolonged stay at high altitude and, hence, under reduced oxygen availability (hypoxia) is associated with a lower concentration of blood glucose ("blood sugar"). It was the aim of the present research project to clarify in mice, if and via which mechanism impaired oxygen availability reduces blood glucose. First, we compared mice maintained under hypoxia to such under normal air (oxygen content 10% versus 21%). After one to two weeks we detected a hypoxia-induced reduction in blood glucose and we showed that this response was independent of differences in body weight. In the next step we corroborated previous speculations that the lowering of blood glucose was mediated by an increase in circulating erythropoietin (EPO). The production of EPO is promoted by oxygen shortage and its most important effect is stimulation of the production of erythrocytes (red blood cells) in bone marrow and spleen. The amount of erythrocytes in the blood is also referred to as the hematocrit with a high hematocrit enhancing oxygen transport, which led to misuse of EPO for doping purposes in endurance sports. Apart from this, there is evidence that EPO influences glucose and lipid metabolism via direct actions on organs like brain, adipose tissue, and muscle. At variance to current assumptions, however, our research showed that the effects of hypoxia and EPO on these organs were not responsible for the observed lowering of blood glucose, which was rather secondary to the high hematocrit. In one of our experiments substantiating the role of the hematocrit, e.g., we infused mice with donor erythrocytes (comparable to a blood transfusion in medicine), which caused an immediate fall in blood glucose. Despite blood glucose and hematocrit being determined in countless routine examinations of human patients, their direct connection has so far remained unnoticed. Nevertheless, this connection provides a plausible explanation for observations of reduced blood glucose in humans with an increased hematocrit. Apart from a stay at high altitude, this association can occur in smokers, in certain disease states (e.g. Polycythemia vera) and under medical treatment with EPO or testosterone. For a huge dataset from young, healthy military conscripts we showed that smoking is not only with a higher hematocrit (as previously known) but also with lower blood glucose. In summary, our research thus discovered a previously unknown factor in the regulation of blood glucose, which is of relevance to several conditions and disease states.