Editors' ChoicePhysiology

An innate ability to resist obesity

Sci. Signal.  17 Mar 2015:
Vol. 8, Issue 368, pp. ec59
DOI: 10.1126/scisignal.aab1141

Systemic inflammation is linked to obesity and metabolic diseases, and various immune cells affect the metabolic activity of adipose tissue. Group 2 innate lymphoid cells (ILC2s), which are induced by interleukin-33 (IL-33) and distinguished from other ILCs by the subset of cytokines they produce, may limit obesity in mice. Brestoff et al. found that ILC2s were present in the abdominal subcutaneous white adipose tissue (WAT) of both obese and non-obese human donors and in the epididymal WAT of obese and non-obese mice, but were more abundant in the samples from non-obese individuals of both species. Compared to wild-type controls, mice lacking IL-33 had fewer ILC2s in the epididymal and inguinal WAT depots. Mice lacking IL-33 also had more epididymal and inguinal WAT, greater overall body size and whole-body adiposity, and impaired glucose sensitivity compared to controls. Conversely, treating wild-type mice reared on a normal diet with IL-33 increased the abundance of ILC2s in epididymal and inguinal WAT and reduced overall adiposity. In wild-type mice that were fed a high-fat diet, IL-33 treatment also increased the abundance of ILC2s in the epididymal WAT, reduced obesity, and improved glucose sensitivity. Based on cellular morphology and expression of the brown and beige fat–specific marker Ucp1 in IL33-/- mice and in mice that received ILC2 transplants, ILC2s, through an IL-33–dependent process, promoted the conversion of white adipocytes into beige adipocytes, which are more metabolically active than white adipocytes. Transcriptomic analysis indicated that expression of a gene encoding an endopeptidase involved in processing prohormones and the gene encoding its target proenkephalin A (Penk) were enriched in ILC2s compared to another ILC subtype. Penk is proteolytically processed to generate opioid-like peptides such as methionine-enkephalin (MetEnk). Treating mice with MetEnk promoted the formation of beige fat and reduced the mass of inguinal WAT in wild-type mice. Application of MetEnk also stimulated expression of Ucp1 in cultured white adipocytes. Thus, ILC2s may limit obesity by producing MetEnk that promote the conversion of fat-storing white adipocytes into metabolically active, fat-burning beige adipocytes.

J. R. Brestoff, B. S. Kim, S. A. Saenz, R. R. Stine, L. A. Monticelli, G. F. Sonnenberg, J. J. Thome, D. L. Farber, K. Lutfy, P. Seale, D. Artis, Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242–246 (2015). [PubMed]