The rise in rates of diabetes and cardiovascular disease has been linked to obesity, and there is lack of effective drug treatments for these conditions

Human infants have large amounts of heat-generating brown fat to protect them from extreme cold, and scientists recently discovered that adult humans retain small amounts of brown fat consisting mainly of a subtype known as beige fat. Cold exposure or exercise can activate brown or beige fat, which burn stored calories and protect mammals from hypothermia, obesity, and metabolic problems. Despite their therapeutic potential for treating these conditions, relatively little was known about the molecular pathways that trigger the formation of these good types of fat.
To address this question in the new study, Spiegelman and Rajesh Rao of the Dana-Farber Cancer Institute and Harvard Medical School focused on a recently identified protein called PGC-1alpha4, which promotes muscle growth in response to resistance exercise. They discovered that PGC-1alpha4 stimulates the secretion of a newly identified hormone called meteorin-like (Metrnl), which is released into the bloodstream and produced in muscle tissue after exercise and in fat tissue after cold exposure in mice.
By converting energy-storing white fat to calorie-burning brown or beige fat, Metrnl increases energy expenditure and improves metabolic health in obese, diabetic mice. This hormone, which could potentially be suitable as a new therapy for obesity and diabetes, exerts these positive effects through activation of immune molecules called interleukin-4 and interleukin-13, as well as immune cells called macrophages located in fat tissue.
In another study published in the same issue, further light is shed on the question of immune responses and obesity by senior author Ajay Chawla of the University of California, San Francisco, who was motivated by his recent findings implicating the immune system in activating brown fat in response to cold environments. Chawla and his team have now revealed the circuit underlying beige fat activation in mice. They found that interleukin-4/13 signaling activated macrophages in white fat tissue, leading to the production of nervous system molecules required for converting white fat to beige fat. These findings reveal important new insights into how the immune system and nervous system work together to stimulate beige fat formation.
Moreover, the researchers found that mice with impaired signaling in this immune pathway produced less beige fat, showed lower energy expenditure, and were unable to maintain their body temperature in cold environments compared with normal mice. By contrast, treatment with interleukin-4 increased the formation of beige fat, reduced body weight, and improved metabolic health in obese mice.
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