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A new role for a class of immune cells in regulating beige fat development

Two studies revealed a critical role for an immunological cell type, called ILC2 cells, in the development and activity of calorie-burning beige fat.  Mammals harbor different kinds of adipose (fat) tissue in various regions of the body.  White adipose tissue (WAT)—the most abundant type of fat—stores calories, while brown adipose tissue burns calories to generate heat.  A third, calorie-burning type of fat, called beige fat, emerges within WAT depots—a process referred to as “browning” of WAT—in response to cold exposure, nervous system triggers, or muscle activity.  The metabolic potential of beige fat has led many scientists to believe that it could serve as a target for treatment strategies for obesity and associated metabolic diseases in humans, but the mechanisms controlling beige fat induction are not well understood. 

Previous research showed that molecular signals from certain immunological cells within WAT activate pathways that induce beige fat formation.  One such signal, called IL-33, has been shown to be present in WAT, and to protect mice from insulin resistance and other metabolic conditions associated with obesity.  In an effort to further understand the role of IL-33 in weight gain and metabolism, two research teams recently discovered that, in mice, a type of immune cells, called group 2 innate lymphoid cells (ILC2s), which are known to respond to IL-33, plays an essential role in beige fat induction and energy balance—the state of balance between energy consumption (eating food), energy storage (fat), and energy expenditure (burning fat to fuel activity and generate body heat). 

In one study, scientists treated male and female mice with IL-33 and found a robust induction of beige fat cells within areas of WAT under the skin (subcutaneous WAT depots).  When exposed to cold temperature, which triggers the browning of WAT, IL-33-treated mice exhibited a greater increase in overall calorie burning (whole-body energy expenditure) than did untreated mice.  The researchers then used mice that were genetically modified to produce a fluorescent “marker” protein exclusively in ILC2s, enabling the scientists to track the formation of these cells as they arise.  IL-33 treatment in these mice led to dramatic induction of active ILC2s as compared to untreated mice.  In addition, the scientists found that IL-33 treatment led to increased numbers of “adipocyte precursor” cells—cells that could either develop into white or beige fat cells, depending on what signals they receive—in WAT.  These precursor cells were characterized and shown to exhibit molecular hallmarks of beige fat, indicating that IL-33 triggers the expansion of adipocyte precursor cells in WAT that are committed to becoming beige fat cells.  Moreover, IL-33 treatment in mice genetically modified to lack ILC2s failed to stimulate production of the precursor cells and beige fat cells, indicating a crucial role for ILC2s in the browning of WAT.  Together, these results show that IL-33 induces ILC2s in WAT, which promotes the browning of WAT through the expansion of beige fat-committed adipocyte precursor cells.  Based on additional experiments in this study and research from other scientists, it is likely that this newly identified pathway works in parallel with other cells and molecules to induce the browning of WAT.

In a separate study, scientists independently demonstrated that IL-33 induces ILC2s in WAT, and further addressed the role of these cells in energy balance using male mice.  The scientists fed mice a high-fat diet, which leads to obesity, and found that WAT from the resulting obese mice contained fewer ILC2s than did normal-weight mice.  Mice genetically modified to lack IL-33 gained more weight and fat mass on a normal diet than did normal mice.  In addition, mice lacking IL-33 had far fewer beige fat cells within WAT than did normal mice.  Mice genetically engineered to lack ILC2s, when treated with IL-33, failed to induce browning of WAT.  However, when ILC2s from normal donor mice were transplanted into mice lacking ILC2s, the browning phenomenon in WAT was restored.  To identify the possible “browning” signals sent from ILC2s, the researchers compared the genes turned on in mouse ILC2s to those turned on in similar cells (ILC3s) that are not involved in the induction of beige fat.  The analysis revealed one gene specific to ILC2s, whose protein product can activate a potential signal called methionine-enkephalin (or MetEnk).  IL-33 treatment led to increased production of MetEnk by ILC2s.  Mice treated with MetEnk exhibited increased browning of WAT, as well as increased body energy expenditure.  Isolated WAT cells treated with MetEnk turned on beige fat genes, suggesting that MetEnk itself can directly promote the browning of WAT.  To begin to address whether ILC2s similarly function in people, the scientists compared WAT biopsies from a small number of donors.  They found that WAT from people who were obese (six women and one man) contained significantly lower levels of ILC2s than did WAT from people of normal weight (three women and four men). 

Together, these studies suggest that IL-33 induces production of ILC2s in WAT.  ILC2s then generate MetEnk, which signals the formation and activity of beige fat cells.  Based on previous research, it is clear that these cells and signals work together with other immune cell pathways to induce the browning of WAT.  While preliminary experiments revealed a correlation between larger numbers of ILC2s and lower body weight in people, additional studies will be needed to continue elucidating the roles of these cells and proteins.  If human beige fat development works in a similar manner, IL-33, ILC2s, MetEnk, and their partners and pathways could be useful therapeutic targets to protect against obesity and metabolic diseases.

Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, and Artis D.  Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity.  Nature 519: 242-246, 2015.

Lee M-W, Odegaard JI, Mukundan L, Qui Y, Molofsky AB, Nussbaum JC, Yun K, Locksley RM, and Chawla A.  Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160: 74-87, 2015.