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Immune system

Weight-loss strategy focused on the immune system

Two signalling molecules secreted by cells of the immune system trigger the conversion of fat-storing white fat cells to fat-burning beige fat cells

Calorie-burning brought on by cold temperatures can be achieved biochemically, which may result in a new weight-loss strategy focused on the immune system rather than the brain, according to a study by UC San Francisco researchers.

It has always been thought that nutrient and energy metabolism has largely been thought to be under the control of the brain and endocrine system. These  results are likely to further fuel the quest to identify new ways to pharmaceutically tame obesity by targeting how much energy we burn, not just how many calories we ingest.

Discussing their findings in the journal Cell, they report two signalling molecules secreted by cells of the immune system trigger the conversion of fat-storing white fat cells to fat-burning beige fat cells.

Working with mice, the team discovered that these signalling molecules, interleukin 4 and interleukin 13, activate cells known as macrophages that in turn drive the fat conversion. In one experiment the researchers gave interleukin 4 to fat mice, which increased beige fat mass, leading to weight loss.

The finding builds on previous work by the researchers who reported in 2011 in Nature that cold activates part of the immune system, and specifically activates interleukin 4 in fat.

In this study, they determined that both interleukin 4 and interleukin 13 recruit macrophages to fat and that the production of molecules called catecholamines by the macrophages causes the browning of white fat.

When the researchers inhibited interleukin 4 signaling in white fat, they found that the mice made less beige fat, burned less energy, and could no longer maintain normal body temperature in the cold.

The new discovery is surprising, the researchers said, because it makes it clear that this control mechanism for fat burning bypasses components of the autonomic nervous system that govern many physiological adaptations.

In comparison to the nervous system, the immune pathway might be more easily manipulated to increase energy expenditure.

Humans and other mammals shiver to keep warm, but cold also triggers the growth of fat cells that burn fuel, instead of the fat cells that store it. Keep humans indoors at 61 degrees to 63 degrees Fahrenheit and they lose weight, research shows. This is because they adapt by generating more fat-burning cells to help them keep warm.

In contrast to the power-converting mechanisms in white fat cells, the gears in the power plants within fat-burning fat cells spin inefficiently. This causes them to burn more energy and generate heat. The trigger for this accelerated fat burning is the activation mitochondria, a protein called uncoupling protein 1 (UCP1).

Cells with UCP1 are capable of heat generation and fat burning, and are known as brown fat or beige fat, depending on the tissue from which they originate. They have more mitochondria than white cells and therefore have a darker tinge.

Although the researchers now believe that the potential to exploit brown fat for weight loss is significant, the amount of individual variation when it comes to brown fat reserves and the potential to generate more brown fat is unclear.

The research was funded by the National Institutes of Health and the American Heart Association.

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