How high altitude changes the body's metabolism

Compared to those who live at sea level, the 2 million people worldwide who live above an elevation of 4,500 meters (14,764 feet) — about the height of Mount Rainier, Mount Whitney, and many Colorado and Alaska peaks — have lower rates of metabolic diseases, such as diabetes, coronary artery disease, hypercholesterolemia and obesity.

Now, the work of U.S. National Science Foundation-supported researchers at Gladstone Institutes has shed new light on this phenomenon. The scientists showed that exposure to chronically low oxygen levels, such as those experienced at high elevation, rewired how mice burn sugars and fats. The results, published in the journal Cell Metabolism, help explain the metabolic differences of people who live at high altitude, and could lead to new treatments for metabolic disease.

"When an organism is exposed to chronically low levels of oxygen, different organs reshuffle their fuel sources and their energy-producing pathways," says Isha Jain, senior author of the new study. "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, where a third of the world's population lives, oxygen makes up about 21% of the air we breathe. But people who live above 4,500 meters, where oxygen makes up just 11% of the air, can adapt to the shortage of oxygen — known as hypoxia — and thrive.

Researchers studying the impact of hypoxia have usually carried out their research in isolated cells or in cancerous tumors, which often lack oxygen. Jain's group wanted a better look at how long-term hypoxia impacts organs throughout the body.

Jain and colleagues at Gladstone and University of California, San Francisco, housed adult mice in pressure chambers containing 21%, 11% or 8% oxygen — all levels at which humans and mice can survive. Over three weeks, the researchers observed the animals' behavior, monitored their temperature, carbon dioxide levels and blood glucose, and used positron emission tomography (PET) scans to study how different organs consumed nutrients.

In the first days of hypoxia, the mice living in 11% or 8% oxygen moved around less, spending hours completely still. By the end of the third week, however, their movement patterns had returned to normal. Similarly, carbon dioxide levels in their blood — which usually decrease when mice or humans breathe faster to try to get more oxygen — initially decreased but returned to normal levels by the end of the three weeks.

The animals' metabolism, however, seemed more permanently altered by the hypoxia. For animals housed in the hypoxic cages, blood glucose levels and body weight both dropped, and neither returned to pre-hypoxic levels.

These changes mirror those in humans who live at high altitudes, and are associated with a lower risk of diseases, including cardiovascular disease. Understanding how hypoxia contributes could lead to new drugs that mimic these beneficial effects.