The IL-4 Brown Out

Immune cell activation promotes thermogenesis in white fat. Thermogenesis is the process of generating body heat in response to cold exposure. In hibernating mammals and human infants, which do not shiver, thermogenesis occurs in brown adipose tissue (BAT). Adult humans lack BAT; however, subcutaneous white adipose tissue (WAT) contains a subset of “beige” adipocytes that become thermogenic during chronic bouts of exposure to cold. Additionally, acute exposure to cold stimulates type II macrophages to secrete catecholamines, which promote thermogenesis in WAT. Using different approaches, Rao et al. and Qiu et al. identified signals that promote immune cell activation in WAT. Mice with muscle-specific overexpression of PGC-1α4 (a splice isoform of the transcriptional coactivator PGC-1α) have increased muscle size and whole-body energy expenditure. Rao et al. identified the hormone meteorin-like (Metrnl) by analyzing transcriptomic and proteomic data from myotubes of these mice. Acute cold exposure increased the expression of Metrnl in mouse BAT and WAT, but not muscle tissue. Experimentally increasing circulating Metrnl in mice promoted the expression of genes associated with thermogenesis in BAT and WAT and increased whole-body energy expenditure. Locally increasing Metrnl in WAT increased the number of type II macrophages and the expression of genes encoding the cytokines IL-13 and IL-4, which is predominantly produced by eosinophils. Genetic ablation of eosinophils or disruption of IL-13 and IL-4 signaling prevented the ability of experimentally increased circulating Metrnl to induce activation of macrophages and production of catecholamines and increase the expression of thermogenic genes in WAT. Acute cold exposure increased the number of eosinphils and the amount of IL-13 and IL-4 in WAT, and injection with a Metrnl-blocking antibody prevented these effects and the ability of cold to induce the expression of thermogenic genes. Similarily, Qiu et al. found that when exposed to cold, mice in which IL-13 and IL-4, the IL-4 receptor, or STAT6 was knocked out or mice with genetic ablation of eosinphils had reduced oxygen consumption, lower body temperature, and reduced abundance of thermogenic proteins in WAT. Additional genetic experiments showed that the presence of the IL-4 receptor on monocytes (macrophage precursor cells), activation of type II macrophages, and the ability of type II macrophages to produce catecholamines was required for thermogenesis in WAT. Injection of IL-4 in wild-type, but not IL-4 receptor-knockout, mice in a thermoneutral environment increased the abundance of thermogenic proteins in WAT, the volume of BAT and beige WAT, and oxygen consumption. Increased energy expenditure during exercise is an effective means of combatting obesity in humans. Injection of IL-4 in mice fed with a high-fat diet reduced blood glucose, improved insulin sensitivity, and reduced total body mass and the percentage of fat mass. Thus, signals that promote the browning of WAT may be potential therapeutic targets for metabolic disease (see Lee and Tontonoz). R. R. Rao, J. Z. Long, J. P. White, K. J. Svensson, J. Lou, I. Lokurkar, M. P. Jedrychowski, J. L. Ruas, C. D. Wrann, J. C. Lo, D. M. Camera, J. Lachey, S. Gygi, J. Seehra, J. A. Hawley, B. M. Spiegelman, Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014). [Pubmed] Y. Qiu, K. D. Nguyen, J. I. Odegaard, X. Cui, X. Tian, R. M. Locksley, R. D. Palmiter, A. Chawla, Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292–1308 (2014). [Pubmed] S. D. Lee, P. Tontonoz, Eosinophils in the fat: Pink is the new brown. Cell 157, 1249–1250 (2014). [Pubmed]