Recent research reveals that during short-term hunger (less than 2 hours), the body doesn’t immediately switch to burning fat. Instead, it first uses glutamine and other non-fat energy sources to meet its energy needs. This process is regulated by the AMPK-activated PDZD8-GLS1 axis, which ensures that cells can maintain energy balance when glucose is scarce. Only after prolonged fasting (over 8 hours) does the body gradually begin to tap into fat reserves. The findings deepen our understanding of cellular energy management and offer new insights into the treatment of metabolic diseases like obesity and diabetes.
It’s a common belief that when you feel hunger pangs during a diet, your body is burning fat. However, recent findings show that the body doesn’t immediately switch to “fat-burning mode” during short periods of fasting. Instead, it undergoes a complex energy regulation process at the cellular level.
With popular weight-loss methods like "ketogenic diets" and "intermittent fasting" gaining attention, they emphasize shifting the body’s energy source from glucose to alternative fuels, such as fatty acids or amino acids. This raises the question: how do our cells respond to these changes on a microscopic level?
A recent study delves into the role of AMP-activated protein kinase (AMPK) in metabolic adaptation during fasting. The researchers found that during short-term fasting (less than 2 hours), the body first uses non-fat energy sources like glutamine. Only after prolonged hunger does the body gradually increase fat oxidation and potentially use unstable proteins to meet its energy demands.
When we eat, our bodies act like savvy financial managers, storing calories and sugars from food for later use. Glucose, the body’s primary energy source, is converted into glycogen and stored in the liver, or it’s transformed into fat throughout the body. When we fast or go without food for a longer period, these reserves become essential, as the body releases stored glucose to maintain energy levels for essential activities.
Various physiological factors, including fasting, cause a drop in blood glucose as glycogen stores are depleted. To maintain energy balance, the body must adapt metabolically, with AMPK playing a central role in this process. AMPK acts as an energy sensor, responding to changes in AMP and ADP levels to regulate energy states. It is especially sensitive to drops in blood glucose and triggers metabolic processes like fat burning while inhibiting new fat synthesis, promoting ATP generation and reducing its consumption. Despite its critical role, scientists are still exploring the precise mechanisms governing the use of alternative energy sources.
The study aimed to understand how cells switch energy sources when glucose is scarce, with a particular focus on the use of glutamine and fatty acids. To investigate, the team labeled mouse embryonic fibroblasts (MEFs) with palmitic acid (a fatty acid) and glutamine to track these molecules during hunger.
The results showed that glutamine breakdown occurs before fatty acid oxidation (FAO) in response to glucose deprivation. Specifically, within just 2 hours of fasting, glutamine utilization increased significantly, while palmitic acid utilization lagged behind. Remarkably, even though glucose was replaced by glutamine, the total levels of TCA cycle intermediates remained largely unchanged. This suggests that when glucose is unavailable, cells quickly switch to using glutamine to maintain energy production instead of immediately resorting to fatty acids.
Figure 1: Under low glucose conditions, glutamine breakdown precedes FAO increase
In line with isotope labeling experiments, the researchers observed a marked increase in oxygen consumption rate (OCR) in both MEFs after 2 hours of fasting and mouse skeletal muscle tissues after 8 hours. This strongly supported the idea that glutamine is the primary fuel source, not fatty acids, during short-term hunger, ensuring that energy supply is maintained.
Figure 2: AMPK promotes mitochondrial-ER binding under low glucose conditions
Further exploration into how AMPK facilitates glutamine utilization under low-glucose conditions revealed that AMPK not only reduced the number of pure mitochondria in glucose-deprived MEFs but also activated a new substrate, PDZD8. This substrate, through a lysosomal glucose-sensing pathway, was phosphorylated by AMPK at T527, which relieved its inhibition and allowed it to interact with GLS1, a key enzyme in glutamine metabolism. This interaction promoted the breakdown of glutamine, ahead of fatty acid oxidation.
Figure 3: AMPK-PDZD8 axis promotes OCR during early starvation
Additionally, the study highlighted the significance of glutamine metabolism in immune responses. Cells exposed to LPS (lipopolysaccharide), which lowers blood sugar rapidly, rely on glutamine to sustain energy production, even during extreme stress conditions. AMPK activation can enhance the protective effects of GLS1 inhibitors, preventing death from LPS-induced hypoglycemia.
Figure 4: AMPK-PDZD8 axis promotes GLS1 activity in permeabilized cells
Conclusion
This research uncovers a vital cellular mechanism—the AMPK-PDZD8-GLS1 axis—critical for maintaining energy balance under low-glucose conditions. During short-term fasting, this system activates, prioritizing glutamine as a substitute energy source to ensure that cells continue to function normally. Specifically, AMPK enhances the collaboration between PDZD8 and GLS1, accelerating glutamine breakdown, thus compensating for glucose deficiency and potentially triggering additional biological functions, such as immune responses.
In simpler terms, during brief fasting or reduced food intake, your body doesn’t immediately switch to burning fat. Instead, it first taps into the glutamine stored in your body. It is only after longer periods of hunger (typically beyond 8 hours) that the body begins to burn fat stores, and in extreme cases, it may even break down some proteins to meet energy needs.
This discovery deepens our understanding of how the body manages energy and opens doors for potential new treatments for metabolic diseases such as obesity and diabetes.