Macrophages increase body temperature...brown fat.

1. NEWS & VIEWS doi:10.1038/nature10714
P H YSIO LO GY
Immune cells fuel the fire
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.
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 form
A
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 not
less of their environment. This essential task maintain their core body temperature in the
Brain
is performed by brown fat tissue1–3. Whereas cold; and they would probably have died
white 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 caused
mitochondria, cellular powerhouses, that by a problem in brown fat: white fat tissue
can convert stored fat directly into heat Nervous system did not respond to nervous stimulation by
through the process of thermo genesis4. releasing lipids into the bloodstream and so
To avoid energy wastage, this happens did not provide fuel for thermogenesis in
only when neurons connected to brown the brown fat (Fig. 1).
Catecholamines
fat release chemical messengers called In obese people, macrophages in white fat
catecholamines. But neurons do not seem Anti-in ammatory tend to show increased pro-inflammatory
macrophage
to be the only regulators of thermogenesis. activity9 and have been linked to insulin
In a paper published on Nature’s web- resistance and diabetes. In light of Nguyen
site today, Nguyen et al.5 show that a Lipids
and colleagues’ data, it might be that
Brown fat
subset of immune-system cells called tissue
pro-inflammatory macrophages cause a
macrophages is also essential for heat detrimental response in obese states in
Alternative
production in brown fat. activation which the fat tissue is under increasing
Thermogenesis is fundamental to the pressure to expand. As fat cells become
ability 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 to
In 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 into
dence for a similar relationship between anti-inflammatory forms. In the absence
thermogenesis 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 efficiently
tissue 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 dysregulated
equally 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 fat
become 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.
6,7
muscle, 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 macrophages
in the body. Being highly mobile, they infil- to enhance and sustain the thermogenic response. to mediate the appropriate peripheral
trate 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 often
To fight pathogens, macrophages are trans- of alternatively activated macrophages in one manipulated to create a range of models from
formed 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 is
proteins, catecholamines regulate the inten- placed mice in a cold environment and found based on the manipulation of macrophages
sity 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 they
in 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. RESEARCH NEWS & VIEWS
doi:10.1038/nature10714
secondary 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, 1509–1517
central 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, 245–255
activated 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, 1796–1808
respect, this specialized, widely distributed e-mails: ajw232@medschl.cam.ac.uk; (2003).
group of cells could represent a novel target ajv22@cam.ac.uk 10. Prieur, X. et al. Diabetes 60, 797–809 (2011).
2 | NAT U R E |
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