How are mitochondria related to obesity?

Recall from the opening of this chapter that brown fat is adipose tissue with a high concentration of mitochondria, which have iron-containing pigments. The uncoupling protein UCP1, found in the inner membranes of mitochondria in brown fat cells, uncouples mitochondrial electron transport (oxidation) and ATP production (phosphorylation), so that instead of being trapped as chemical energy in the formation of ATP, the energy released by oxidation is released as heat.

Hibernating animals take advantage of the heat emitted by the catabolism of energy-rich molecules in brown fat, especially when aroused. In hibernating animals, brown fat and UCP1 increase during the winter. It turns out that adult humans also experience a seasonal variation in brown fat, having more of it in the cooler months. Other factors such as diet and exercise being equal, increased fat catabolism occurs in the presence of UCP1 (as demonstrated by the experiment in Investigating Life: Mitochondria, Genetics, and Obesity).

Genetic studies confirm the role of UCP1 in fat breakdown as well. For example, some people have a genetically determined variant of UCP1 that has lower uncoupling activity than normal UCP1. As people with the variant get older, they accumulate more body fat than their peers with normal UCP1 do.

Future directions

The recent finding that not just babies but also adults have mitochondria-laden brown fat has sparked interest in the possible activation of these cells to treat obesity. In addition to occurring in well-known locations such as the neck and shoulders, brown fat cells have been found mixed in with non–brown fat all over the body, and can be seen by PET (positron emission tomography) scans. At the U.S. National Institutes of Health, a research team led by Aaron Cypess has found unexpectedly that a drug used to treat people with an overactive bladder also activates fat breakdown in brown fat cells. The drug, mirabegron, targets a receptor on bladder cells that is also expressed on brown fat cells. When people without bladder disease were given this drug, brown fat cells were activated. There was increased glucose uptake and heat production due to mitochondrial uncoupling, and also an eightfold increase in fatty acid breakdown by the mitochondria. This could be a promising treatment for disorders that lead to obesity.