Over 2 million people around the world live at high altitude - above 4,500 meters (or 14,764 feet) of elevation, and compared to people who live at sea level, these individuals have lower rates of metabolic disorders such as coronary artery disease, diabetes, hypercholesterolemia, and obesity. Scientists investigated this observation, and found that there are significant metabolic changes that occur when a mouse model lives under different oxygen conditions. The findings, which have been reported in Cell Metabolism, could help us learn more about cellular metabolism and treating metabolic disease.
Under conditions of chronically low oxygen, various organs alter their sources of fuel and their biochemical pathways that generate energy, said senior study author Isha Jain, PhD, a Gladstone Assistant Investigator. "We hope these findings will help us identify metabolic switches that might be beneficial for metabolism even outside of low-oxygen environments."
At sea level, about 21 percent of the air is oxygen. But over 4,500 meters, that level drops to just 11 percent, a low level that is called hypoxic. People can adapt to the change, however.
In this study, mice lived for three weeks in pressure chambers with different, survivable levels of oxygen: 21 percent, 11 percent, or 8 percent. The behavior, temperature, blood glucose, and carbon dioxide levels of the mice were observed; and PET scans were used to assess nutrient consumption in different organs.
While mice living in hypoxic conditions of 8 or 11 percent oxygen did not move nearly as much as the mice in 21 percent oxygen for the first few weeks, and the levels of carbon dioxide in the blood of the hypoxic mice decreased at first, their movement and blood carbon dioxide normalized by the end of the third week. Blood carbon dioxide levels decrease when mice or humans breathe faster in an attempt get more oxygen.
The metabolism of the hypoxic mice seemed to be altered in a permanent way, however; their blood glucose and body weight decreased and never returned to the levels seen in mice housed in 21 percent oxygen. The study authors noted that these changes appear to mimic what's seen in people living at high altitude.
The PET scans also revealed evidence of lasting changes. The body uses a lot of oxygen in the metabolism of fatty acids and amino acids, and less oxygen when metabolizing glucose.
Hypoxia caused an increase in glucose metabolism in most organs, which was not surprising. But in brown fat and skeletal muscle, which both metabolize high levels of glucose, the consumption of glucose was actually reduced.
"Prior to this study, the assumption in the field was that in hypoxic conditions, your whole body's metabolism becomes more efficient in using oxygen, which means it burns more glucose and fewer fatty acids and amino acids," said Jain. "We showed that while some organs are indeed consuming more glucose, others become glucose savers instead."
This seems to make sense, noted Jain, because isolated cells won't have to make a tradeoff to spare glucose, but a whole animal will to survive.
This study has shown that low oxygen levels can promote reduced body weight and lower blood glucose levels, which may explain why high altitude living seems to have a beneficial impact on human health.
The researchers are continuing to investigate, and are hoping to identify some of the cell types and signaling molecules that are involved in these physiological changes.
Sources: Gladstone Institutes, Cell Reports
