Through their research study, they showed how chronically low oxygen levels, such as those experienced at high elevations, change the way mice burn sugars and fats. Carbon dioxide levels in the blood– which reduce when mice or human beings breathe faster to attempt to get more oxygen– initially reduced but returned to normal levels by the end of the 3 weeks.
For animals housed within the hypoxic cages, blood glucose levels and body weight both dropped, and neither returned to pre-hypoxic levels. To metabolize fatty acids (the structure blocks of fats) and amino acids (the building blocks of proteins), the body requires high levels of oxygen, while less oxygen is needed to metabolize the sugar glucose. The scientists discovered that in brown fat and skeletal muscle– 2 organs that are already understood for their high levels of glucose metabolic process– levels of glucose intake rather went down.
A team of researchers in Isha Jains laboratory at Gladstone Institutes showed how chronically low oxygen levels, such as those experienced at 4,500 meters of elevation, rewire how mice burn sugars and fats. Credit: Michael Short/Gladstone Institutes
When mice are subjected to continual, low levels of oxygen comparable to those discovered at an altitude of 4,500 meters, their metabolic process modifications.
In contrast to individuals residing at sea level, the 2 million individuals worldwide living at an elevation of 4,500 meters or higher (equivalent to the height of peaks such as Mount Rainier, Mount Whitney, and numerous peaks in Colorado and Alaska) have a lower incidence of metabolic diseases such as diabetes, coronary artery hypercholesterolemia, disease, and obesity.
Researchers at the Gladstone Institutes have now shed light on this interesting phenomenon. Through their research study, they demonstrated how chronically low oxygen levels, such as those experienced at high elevations, alter the method mice burn sugars and fats. The findings, published in the journal Cell Metabolism, not only provide insights into the metabolic differences of individuals residing at high elevations but also lead the way for the advancement of novel treatments for metabolic illness.
” When an organism is exposed to chronically low levels of oxygen, we found that different organs reshuffle their fuel sources and their energy-producing pathways in numerous methods,” states Gladstone Assistant Investigator Isha Jain, Ph.D., senior author of the brand-new study. “We hope these findings will assist us determine metabolic switches that might be useful for metabolism even outside of low-oxygen environments.”
Simulating High Altitude Living
Around water level, where a third of the worlds population lives, oxygen comprises about 21 percent of the air we breathe. However individuals who live above 4,500 meters, where oxygen makes up just 11 percent of the air, can adjust to the scarcity of oxygen– referred to as hypoxia– and thrive.
Scientists studying the effect of hypoxia have usually performed their research in isolated cells or within cancerous tumors, which often do not have oxygen. Jains group wanted a more nuanced look at how long-lasting hypoxia impacts organs throughout the body.
” We wished to profile the metabolic changes that take place as an organism adapts to hypoxia,” states Ayush Midha, a college student in Jains laboratory and the first author of the new paper. “We believed this might offer some insight into how that adaptation secures versus metabolic disease.”
Midha, Jain, and their associates at Gladstone and UC San Francisco (UCSF) housed adult mice in pressure chambers including either 21 percent, 11 percent, or 8 percent oxygen– all levels at which both people and mice can make it through. Over 3 weeks, they observed the animals habits, monitored their temperature level, co2 levels, and blood glucose, and utilized positron emission tomography (PET) scans to study how various organs were consuming nutrients.
Redistributing Fuel
In the very first days of hypoxia, the mice residing in 11 percent or 8 percent oxygen moved less, investing hours completely still. By the end of the 3rd week, however, their movement patterns had actually gone back to regular. Carbon dioxide levels in the blood– which decrease when humans or mice breathe faster to attempt to get more oxygen– initially returned however reduced to typical levels by the end of the 3 weeks.
The animals metabolism, however, appeared more permanently modified by the hypoxia. For animals housed within the hypoxic cages, blood sugar levels and body weight both dropped, and neither returned to pre-hypoxic levels. In basic, these more long lasting modifications mirror what has been seen in humans who live at high altitudes.
When the researchers examined PET scans of each organ, they likewise discovered enduring changes. To metabolize fats (the structure blocks of fats) and amino acids (the foundation of proteins), the body requires high levels of oxygen, while less oxygen is needed to metabolize the sugar glucose. In a lot of organs, hypoxia led to a boost in glucose metabolism– a predicted action to the scarcity of oxygen. The researchers discovered that in brown fat and skeletal muscle– 2 organs that are currently understood for their high levels of glucose metabolic process– levels of glucose usage instead went down.
” Prior to this research study, the assumption in the field was that in hypoxic conditions, your whole bodys metabolism ends up being more effective in using oxygen, which suggests it burns more glucose and less fatty acids and amino acids,” states Jain, who is likewise an assistant professor in the Department of Biochemistry at UCSF. “We revealed that while some organs are certainly taking in more glucose, others end up being glucose savers instead.”
In retrospect, Jain states the observation makes good sense; the separated cells formerly studied do not require to make compromises to conserve glucose, while a whole animal, to survive, does.
The enduring effects of long-term hypoxia seen in the mice– lower body weight and glucose levels– are both associated with a lower threat of diseases in human beings, consisting of heart disease. Understanding how hypoxia adds to these modifications could cause brand-new drugs that imitate these beneficial impacts.
With that goal in mind, Jains group wants to follow up on this deal with studies that look a lot more carefully at how specific cell types and levels of signaling particles alter in different ways with hypoxia. Such research might point towards ways to simulate the protective metabolic results of hypoxia with drugs– or high-altitude journeys.
” We currently see athletes going to train at elevation to improve their athletic performance; possibly in the future, well begin suggesting that people hang out at high altitude for other health reasons,” says Midha.
Recommendation: “Organ-specific fuel rewiring in chronic and severe hypoxia rearranges glucose and fatty acid metabolic process” by Ayush D. Midha, Yuyin Zhou, Bruno B. Queliconi, Alec M. Barrios, Augustinus G. Haribowo, Brandon T.L. Chew, Cyril O.Y. Fong, Joseph E. Blecha, Henry VanBrocklin, Youngho Seo and Isha H. Jain, 7 March 2023, Cell Metabolism.DOI: 10.1016/ j.cmet.2023.02.007.
The research study was funded by the National Institute of General Medical Sciences, the National Institutes of Health, the Defense Advanced Research Projects Agency, the California Institute for Regenerative Medicine, and the National Science Foundation.