Think back to your first ever biology class on mammals. You most likely learned that all mammals, including humans, are warm-blooded (a.k.a., homeotherms) which means that our bodies remain at a constant temperature despite the temperature changes in our environment. So what is it that allows us to maintain this constant body temperature? Answer: thermogenesis.
Thermogenesis, essentially, is the conversion of stored fat into heat (1). We are most familiar with thermogenesis as shivering, which is the (inefficient) conversion of chemical ATP energy into kinetic, then heat energy. For this paper, however, Nguyen, et al. were most interested in non-shivering thermogenesis. The most recent model of thermogenesis dictates that when the hypothalamus senses cold temperatures, it triggers sympathetic discharge, releasing the hormone, noradrenaline, in brown adipose tissue (BAT), and white adipose tissue (WAT) (Fig.1).
Nguyen, et al. found that when mice were exposed to cold temperature, both BAT and WAT activated adipose tissue macrophages that secrete catecholamines, hormones that trigger the fight-or-flight response. However, the effects downstream of catecholamines secretion differ between the two tissue types: catecholamines induce lipolysis in WAT, while in BAT, they induce thermogenic gene expression (4).
Macrophages are like the little ninjas of our immune system—they engulf and kill intracellular pathogen and pathogen components without any particular loyalty to a specific signaling pathway. Given this, they can be activated through two separate pathways: the creatively named classical and alternative activation pathways (3). Our classically activated macrophages, as per their common association, are pro-inflammatory and anti-parasitic in the classical pathway, with the inflammatory antiviral cytokine, IFN-g giving it orders The alternatively activated macrophage, on the other hand, is anti-inflammatory, and pro-survival (Fig. 2). Additionally, alternatively activated macrophages can facilitate wound healing. This pathway does not require priming, like the classical pathway, but often takes its orders from stimuli such as IL-4 and IL-13 (2).
Possibly by assuring PETA that the only reason they were doing this was to save the animals from the summer heat, the authors of this paper exposed mice to the cold by sticking them into cages that had been pre-chilled to 4°. They saw that in BAT and WAT specifically, macrophages were activated in the alternative manner rather than the classical. Through gene expression analysis and flow cytometry, they saw that whereas the genes for alternative activation were progressively increased as the temperature was decreased, the genes for the classical activation were unchanged. Correspondingly, when Nguyen, et al. looked at mice that do not have the IL-4 and IL-13—and so, mice that did not have any choice but to activate macrophages through the classical pathway, they did not see the same increase in gene expression in these mice. They also made sure that this increase in alternative activation was specific to the BAT and WAT by looking for the same reactions in other tissues, including skeletal muscle and liver tissues. The result? No expression of the alternative genes. This indicated that the alternative activation of macrophages was the primary response of just the fat tissues to cold.
Nguyen, et al. noticed that thermogenic genes (Ppargc1a and Ucp1) and beta-oxidation genes (Acox1 and Ascl1) were induced in BAT in wild-type mice that were exposed to the cold. In mice that could not induce the alternative activation of macrophages (and those without any macrophages altogether), they saw that the mice died of hypothermia.
Beta-adrenergic signaling is linked to b-oxidation genes in the WAT. During alternative activation, oxidation triggers the b-adrenergic genes, which then cause free fatty acids to be released into the BAT, thereby fueling respiration (5). This means that with colder temperatures, unless something is being done to externally provide heat, mice will lose weight because their white fats are being dissolved, essentially, so as to provide fuel to the brown fats to keep the body temperature as constant as possible. Accordingly, they saw that mice that could not trigger the alternative activation of macrophages lost less weight than the mice who could when they were exposed to the cold. To support that finding, they also noticed that mice that were able to trigger alternative activation had higher levels of perilipin phosphorylation, which induces a series of chemical cascade events that would eventually lead to the breakdown and release of free fatty acids (6).
Finally, Nguyen, et al., saw that alternative activation of macrophages contributed to thermogenesis by providing the trigger for a bunch of metabolic processes. The first of these processes is the secretion of noradrenaline, which is a catecholamine (7). I had mentioned earlier that catecholamines induce lipolysis in WAT and thermogenesis in BAT. Their experiments show that with increase in temperature comes an increase in the enzyme, tyrosine hydroxylase (Th), which causes the secretion of catecholamine, which is what triggers WAT to send over their free fatty acid to BAT so as to maintain thermogenesis against cold. All of this occurs only in the presence of IL-4, suggesting that it is the alternative activation of macrophages that is in play during this entire process.
This study indicates that the macrophages and cytokines (IL-4) play a large role in thermogenesis, the body’s natural response to the cold. Because these immune cells regulate between white and brown fat cells by dissolving white cells to provide fuel for the brown cells, there is much potential for the development of a natural anti-obesity drug that manipulates this regulatory interaction. In fact, Google “thermogenesis”, and you will receive site upon site of weight-loss drug commercials, all claiming to use thermogenesis as a novel way to help in weight-loss. However, as with all manipulations of natural processes, increasing the level of a particular immune cell might disrupt the action of another. Much research is still to be done regarding the manipulation of the energy exchange regulated by IL-4 and macrophages to intentionally increase weight-loss.
- Nguyen, K.D., et al. 2011. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature. 480:104-108.
2) Stein, M. et al. 1992. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J. Exp. Med. 176:287.
4) Orava, J., et al. 2011. Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin. Cell. 14(2):272-279.
5) Nedergaard, J., et al. 2011. New powers of brown fat: fighting the metabolic syndrome. Cell Metab. 13:238-240
6) Haemmerle, G., et al. 2006. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 312:734-737.