Researchers from the USA have investigated metabolism and energy balance in a Sanfilippo type A mouse model to better understand why patients with MPS conditions, like Sanfilippo, develop cachexia.
Cachexia is a state of negative energy balance that leads to the wasting away of muscles and fat tissue, severe weight loss, weakness and fatigue. Cachexia is a complex symptom, often seen in the more advanced stages of Sanfilippo and many other diseases, and can be hard to treat even with normal food intake or feeding tubes.
To study the metabolism of mice with Sanfilippo type A, the researchers first measured the levels of fats in the blood. When fasting, the mice with Sanfilippo type A had 40% more fats than unaffected mice, and the levels remained high even four hours after a meal. In mice with Sanfilippo type B, the fasting fat levels remained normal, but there were high levels of fats in their blood four hours post-meal.
With further investigation, the team found that these high levels of fats were due to increased absorption of fats in the intestines rather than increased processing in the liver.
To track where the fat from the diet was going in the body, they fed the mice a meal that included ‘molecular labels’ able to be detected in the lab. When mice with Sanfilippo were compared to unaffected mice, most tissues displayed no difference in the concentration of the label, but there was a difference seen in a type of fat tissue known as ‘brown fat’.
White fat is the most common form of fat tissue and stores a lot of energy, whereas brown fat is less widespread in the body and helps to generate heat. By measuring the label, the researchers found the fats in the meal were 2.4-times more likely to be in the brown fat cells of the Sanfilippo type A mice compared to unaffected mice.
When they measured heat production and core body temperatures, Sanfilippo type A mice also showed significant increases compared to unaffected mice, which was not attributed to differences in physical activity. With more detailed examination of the brown fat tissue, the team showed that there was impaired clearance of defective mitochondria in this tissue.
Mitochondria are a part of the cell that can produce energy and heat. The researchers note that the impaired autophagy, which is known to occur in Sanfilippo, may explain the build-up of defective mitochondria.
As a result of this study, the team suggests that the accumulation of mitochondria in brown fat in mice with Sanfilippo type A leads to an increased demand for fats as fuel. The imbalance in energy production may lead to a loss of fat tissue if insufficient fat is consumed in the diet, potentially contributing to the cachexia seen in the disease. The team note that other mechanisms may also contribute to cachexia in Sanfilippo, and further research is needed, especially to understand the clinical relevance of their findings.
The study was led by Associate Professor Philip Gordts and Professor Jeffrey Esko from the University of California, San Diego. It was made possible with multiple sources of funding support, including grants from Cure Sanfilippo Foundation (USA), the National Mucopolysaccharidosis Society (USA), and the National Institutes of Health (USA).
