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Macrophages increase body temperature...brown fat.

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  1. 1. NEWS & VIEWS doi:10.1038/nature10714 P H YSIO LO GYImmune cells fuel the fireRegulation 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.ANDREW J. WHITTLE or that encoding the IL-4 receptor from& A N T O N I O V I D A L- P U I G macrophages — thereby preventing them from adopting the anti-inflammatory formA ll mammals, including humans, are — resulted in striking thermogenic defects. homeotherms — they maintain a The mice could no longer effectively gener- constant body temperature regard- ate heat in their brown fat; they could notless of their environment. This essential task maintain their core body temperature in the Brainis performed by brown fat tissue1–3. Whereas cold; and they would probably have diedwhite fat is an energy storage depot, brown after prolonged exposure to low tempera-fat is equipped with a specialized form of tures. These defects were not solely causedmitochondria, cellular powerhouses, that by a problem in brown fat: white fat tissuecan convert stored fat directly into heat Nervous system did not respond to nervous stimulation bythrough the process of thermo genesis4. releasing lipids into the bloodstream and soTo avoid energy wastage, this happens did not provide fuel for thermogenesis inonly when neurons connected to brown the brown fat (Fig. 1). Catecholaminesfat release chemical messengers called In obese people, macrophages in white fatcatecholamines. But neurons do not seem Anti-in ammatory tend to show increased pro-inflammatory macrophageto be the only regulators of thermogenesis. activity9 and have been linked to insulinIn a paper published on Nature’s web- resistance and diabetes. In light of Nguyensite today, Nguyen et al.5 show that a Lipids and colleagues’ data, it might be that Brown fatsubset of immune-system cells called tissue pro-inflammatory macrophages cause amacrophages is also essential for heat detrimental response in obese states in Alternativeproduction in brown fat. activation which the fat tissue is under increasing Thermogenesis is fundamental to the pressure to expand. As fat cells becomeability of mammals to balance their energy White fat overburdened and begin to die, pro-inflam-requirements with their nutritional stores. tissue matory macrophages would be expected toIn rodents, the effectiveness of this process Heat increase in number to clean up the debris.has implications for how easily the animals IL-4, other Macrophage This could limit the number of macro-become obese, and there is increasing evi- cytokines phages available for transformation intodence for a similar relationship between anti-inflammatory forms. In the absencethermogenesis and body-weight regula- Figure 1 | Role of macrophages in thermogenesis. of sufficient anti-inflammatory macro-tion in humans2. The ability of white fat In response to a reduced environmental temperature, phages, the white fat may not efficientlytissue to release lipids into the bloodstream the brain sends chemical signals (catecholamines) to respond to signals from the central nerv-as required, or remove them from it, is white and brown fat tissues. Catecholamines activate ous system, creating a state of dysregulatedequally crucial. Humans in whom this pro- brown fat to generate heat. The source of energy for lipid release10 and metabolic inflexibility.cess is disturbed through genetic defects heat production is lipids that are released by white fat Beyond the direct implications of these in response to catecholamines and that reach brown fatbecome extremely ill: fat is inappropriately 5 findings5 for energy balance lie far-reaching through the bloodstream. Nguyen et al. report that IL-4,deposited in organs such as the liver, and in and perhaps other cytokines including catecholamines issues for the entire field of animal research. 6,7muscle, leading to diabetes . themselves, drive alternative (anti-inflammatory) Nguyen and co-authors’ observations sug- Macrophages are a frontline defence activation of macrophages in both forms of fat tissue. gest that, in some settings, the central nerv-against anything that should not be present The activated macrophages also secrete catecholamines ous system relies heavily on macrophagesin the body. Being highly mobile, they infil- to enhance and sustain the thermogenic response. to mediate the appropriate peripheraltrate almost every tissue to consume and response to normal physiological demands.dispose of material that might be damaging. roles. Nguyen et al. explore the regulatory role But in animal studies, macrophages are oftenTo fight pathogens, macrophages are trans- of alternatively activated macrophages in one manipulated to create a range of models fromformed into pro-inflammatory machines that such physiological task — thermogenesis. those for Alzheimer’s disease to HIV infec-secrete catecholamines. Along with cytokine To induce thermogenesis, the authors 5 tion. Therefore, any published study that isproteins, catecholamines regulate the inten- placed mice in a cold environment and found based on the manipulation of macrophagessity of the immune response at the site of that the macrophages in the animals’ brown may need to be re-examined, because sci-infection8. However, macrophages also exist and white fat underwent a clear shift towards entists should ask whether the effects theyin alternatively activated, anti-inflammatory the anti-inflammatory form. Removal of observed were the result of direct manipu-forms that have a wide range of physiological the gene encoding the cytokine protein IL-4 lation of the immune system or a result of | NAT U R E | 1 © 2011 Macmillan Publishers Limited. All rights reserved
  2. 2. RESEARCH NEWS & VIEWSdoi:10.1038/nature10714secondary alterations in the activity of the for therapies for obesity and other fat-storage 1. Cypess, A. M. et al. N. Engl. J. Med. 360, 1509–1517central nervous system. disorders. ■ (2009). 2. Ouellet, V. et al. J. Clin. Endocrinol. Metab. 96, Addressing whether such genetic manipu- 192–199 (2011).lations alter how the mouse brain ‘perceives’ Andrew J. Whittle and Antonio Vidal-Puig 3. Saito, M. et al. Diabetes 58, 1526–1531 (2009).its environment is beyond the scope of the are in the Department of Clinical 4. Cannon, B. & Nedergaard, J. Physiol. Rev. 84, 277–359 (2004).present work. Furthermore, Nguyen et al. do Biochemistry, University of Cambridge 5. Nguyen, K. D. et al. Nature http://dx.doi.not explore the proportional contribution of Metabolic Research Laboratories, org/10.1038/nature10653 (2011).macrophages to nervous-system activity. What Institute of Metabolic Science, NIHR 6. Gandotra, S. et al. J. Biol. Chem. 286, 34998–35006 (2011).they do show, however, is that alternatively Cambridge Biomedical Research Centre, 7. Huang-Doran, I. et al. J. Endocrinol. 207, 245–255activated macrophages are key to how the Addenbrooke’s Hospital, Cambridge (2010).body handles and burns its fat stores. In that CB2 0QQ, UK. 8. Flierl, M. A. et al. Nature 449, 721–725 (2007). 9. Weisberg, S. P. et al. J. Clin. Invest. 112, 1796–1808respect, this specialized, widely distributed e-mails:; (2003).group of cells could represent a novel target 10. Prieur, X. et al. Diabetes 60, 797–809 (2011).2 | NAT U R E | © 2011 Macmillan Publishers Limited. All rights reserved