Regulation of body temperature by the nervous system is essential for physiological function in both health and disease. The immune system also seems to have a crucial role in this process. See Letter p.104
All mammals, including humans, are homeotherms — they maintain a constant body temperature regardless of their environment. This essential task is performed by brown fat tissue1,2,3. Whereas white fat is an energy storage depot, brown fat is equipped with a specialized form of mitochondria, cellular powerhouses, that can convert stored fat directly into heat through the process of thermogenesis4. To avoid energy wastage, this happens only when neurons connected to brown fat release chemical messengers called catecholamines. But neurons do not seem to be the only regulators of thermogenesis. On page 104 of this issue, Nguyen et al.5 show that a subset of immune-system cells called macrophages is also essential for heat production in brown fat.*
Thermogenesis is fundamental to the ability of mammals to balance their energy requirements with their nutritional stores. In rodents, the effectiveness of this process has implications or how easily the animals become obese, and there is increasing evidence for a similar relationship between thermogenesis and body-weight regulation in humans2. The ability of white fat tissue to release lipids into the bloodstream as required, or remove them from it, is equally crucial. Humans in whom this process is disturbed through genetic defects become extremely ill: fat is inappropriately deposited in organs such as the liver, and in muscle, leading to diabetes6,7.
Macrophages are a frontline defence against anything that should not be present in the body. Being highly mobile, they infiltrate almost every tissue to consume and dispose of material that might be damaging. To fight pathogens, macrophages are transformed into pro-inflammatory machines that secrete catecholamines. Along with cytokine proteins, catecholamines regulate the intensity of the immune response at the site of infection8. However, macrophages also exist in alternatively activated, anti-inflammatory forms that have a wide range of physiological roles. Nguyen et al. explore the regulatory role of alternatively activated macrophages in one such physiological task — thermogenesis.
To induce thermogenesis, the authors5 placed mice in a cold environment and found that the macrophages in the animals' brown and white fat underwent a clear shift towards the anti-inflammatory form. Removal of the gene encoding the cytokine protein IL-4 or that encoding the IL-4 receptor from macrophages — thereby preventing them from adopting the anti-inflammatory form — resulted in striking thermogenic defects. The mice could no longer effectively generate heat in their brown fat; they could not maintain their core body temperature in the cold; and they would probably have died after prolonged exposure to low temperatures. These defects were not solely caused by a problem in brown fat: white fat tissue did not respond to nervous stimulation by releasing lipids into the bloodstream and so did not provide fuel for thermogenesis in the brown fat (Fig. 1).
In obese people, macrophages in white fat tend to show increased pro-inflammatory activity9 and have been linked to insulin resistance and diabetes. In light of Nguyen and colleagues' data, it might be that pro-inflammatory macrophages cause a detrimental response in obese states in which the fat tissue is under increasing pressure to expand. As fat cells become overburdened and begin to die, pro-inflammatory macrophages would be expected to increase in number to clean up the debris. This could limit the number of macrophages available for transformation into anti-inflammatory forms. In the absence of sufficient anti-inflammatory macrophages, the white fat may not efficiently respond to signals from the central nervous system, creating a state of dysregulated lipid release10 and metabolic inflexibility.
Beyond the direct implications of these findings5 for energy balance lie far-reaching issues for the entire field of animal research. Nguyen and co-authors' observations suggest that, in some settings, the central nervous system relies heavily on macrophages to mediate the appropriate peripheral response to normal physiological demands. But in animal studies, macrophages are often manipulated to create a range of models from those for Alzheimer's disease to HIV infection. Therefore, any published study that is based on the manipulation of macrophages may need to be re-examined, because scientists should ask whether the effects they observed were the result of direct manipulation of the immune system or a result of secondary alterations in the activity of the central nervous system.
Addressing whether such genetic manipulations alter how the mouse brain 'perceives' its environment is beyond the scope of the present work. Furthermore, Nguyen et al. do not explore the proportional contribution of macrophages to nervous-system activity. What they do show, however, is that alternatively activated macrophages are key to how the body handles and burns its fat stores. In that respect, this specialized, widely distributed group of cells could represent a novel target for therapies for obesity and other fat-storage disorders.
*This article and the paper5 under discussion were published online on 20 November 2011.