Longevity Briefs: Fat Breakdown During Fasting Works Differently

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Fasting and other forms of calorie restriction (a sharp reduction in calorie intake without causing malnutrition) appear to be particularly effective strategies for weight loss. With standard dieting strategies, the body’s basal metabolic rate may slow down to compensate for the reduction in calorie intake, avoiding the need to burn as much fat. The primary purpose of white fat (the most abundant type of fat tissue) is to allow an organism to survive a famine, and so fat tissue can be ‘reluctant’ to relinquish its stores if there is an alternative way of balancing the books. This is not an option with fasting – the energy required to keep the heart beating, the neurons firing and so on has to come from somewhere.

Fat cells (adipocytes) store fat primarily in the form of triglycerides. When these stores need to be released into the blood, triglycerides are broken down into their constituent parts (glycerol and fatty acids) by a group of enzymes called neutral lipases. These enzymes control the rate at which fat can be broken down, but something about this didn’t quite make sense to scientists. It had been observed that during fasting, the activity of the genes that encoded neutral lipases increased, but not enough to explain the rate of fat breakdown. Because of this, it was suspected that an alternative way of releasing fat might exist, and these researchers decided to investigate.

The discovery:

Researchers began by observing mice subjected to a 24-hour fasting protocol. They looked at levels of transcription factors in the mice (which indicate which genes are being activated) and found that there was an increase in transcription factors regulating lysosome formation in fat tissue. Lysosomes are small membrane packages within cells that contain enzymes, and are primarily involved in breaking down and recycling waste material. When researchers isolated lysosomes from the fat tissue of fasted mice, they found that the lysosomal preparations contained perilipin, a protein essential for the mobilisation of fat. This suggested that the lysosomes were interacting with fat stores and possibly assisting with triglyceride breakdown.

To test this theory, the researchers used various approaches, including administering drugs that block lysosomal activity and genetic techniques to target lysosome formation. They found that blocking lysosome function in these ways reduced the mice’s ability to mobilise their fat stores when fasting. Further investigation suggested that during the first few hours of fasting, neutral lipases were essential for the rapid breakdown of fat stores. However, as time went on the newly discovered lysosomal pathway became the dominant way in which adipose tissue released its fat stores. Experiments in human adipocytes suggested that a similar lysosomal pathway was also active in humans.

The implications:

This study suggests that the way in which fat tissue releases its fat stores during prolonged fasting is quite different to the pathway normally used to break down fat. Gaining a better understanding of how our bodies adapt to fasting can only be a good thing, and might help us understand why fasting appears to be uniquely beneficial not just for weight loss, but for general health as well. Disruptions in lysosomal genes have been found to be associated with metabolic derangements and diseases like coronary artery disease. Lysosomes appear to play an important role in the ageing process, as their ability to fulfil their main function – breaking down cellular waste such as damaged proteins – declines with age.

Further research is needed to fully understand the nuances of this pathway in humans, but it is already known that fasting increases lysosome activity in general. Increased recycling by lysosomes is just one of the cell’s ways of conserving energy when nutrient intake is low.