Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity

Abstract

Obesity is an increasingly prevalent disease regulated by genetic and environmental factors. Emerging studies indicate that immune cells, including monocytes, granulocytes and lymphocytes, regulate metabolic homeostasis and are dysregulated in obesity1,2. Group 2 innate lymphoid cells (ILC2s) can regulate adaptive immunity3,4 and eosinophil and alternatively-activated macrophage responses5, and were recently identified in murine white adipose tissue (WAT)5 where they may act to limit the development of obesity6. However, ILC2s have not been identified in human adipose tissue, and the mechanisms by which ILC2s regulate metabolic homeostasis remain unknown. Here, we identify ILC2s in human WAT and demonstrate that decreased ILC2 responses in WAT are a conserved characteristic of obesity in humans and mice. Interleukin (IL)-33 was found to be critical for the maintenance of ILC2s in WAT and in limiting adiposity in mice by increasing caloric expenditure. This was associated with recruitment of uncoupling protein 1 (UCP1)+ beige adipocytes in WAT, a process known as beiging or browning that regulates caloric expenditure7–9. IL-33-induced beiging was dependent on ILC2s, and IL-33 treatment or transfer of IL-33-elicited ILC2s was sufficient to drive beiging independently of the adaptive immune system, eosinophils or IL-4 receptor signaling. We found that ILC2s produce methionine-enkephalin peptides that can act directly on adipocytes to upregulate Ucp1 expression in vitro and that promote beiging in vivo. Collectively, these studies indicate that in addition to responding to infection or tissue damage, ILC2s can regulate adipose function and metabolic homeostasis in part via production of enkephalin peptides that elicit beiging.

Obesity-Associated Adipose Tissue Inflammation and Transplantation

“…In lean AT, more than 90% of the IL-5-and IL-13-secreting cells are ILC2s (14,15), and these cytokines work in concert with IL-4 to sustain the normal composition of eosinophils and M2 macrophages. Additionally, ILC2s can directly act on white adipocytes to promote AT browning via IL-13 and the IL-4 receptor (16) or, when stimulated with IL-33, by producing methionine-enkephalin, an opioid-like peptide that promotes browning in an IL-4R-dependent mechanism (17). Notably, antibody-mediated depletion of ILC2s leads to increased weight gain and insulin resistance in mice fed an HFD, while transfer of ILC2s into obese mice results in weight loss (18), demonstrating that ILC2s dominantly regulate AT inflammation.…”

PCR array and protein array studies demonstrate that IL-1β(interleukin-1β) stimulates the expression and secretion of multiple cytokines and chemokines in human adipocytes

“…A notable exception is the hormone adiponectin, with its anti-inflammatory and insulin sensitising actions (Ouchi et al, 1999;Yokota et al, 2000;Berg et al, 2001;Yamauchi et al, 2001), the production and secretion of which falls as fat mass expands (Arita et al, 1999;Hotta et al, 2000). The establishment of an inflammatory state in adipose tissue in obesity, which includes the recruitment of activated macrophages and other immune cells (Weisberg et al, 2003;Xu et al, 2003;Pond, 2005;Bertola et al, 2012;Brestoff et al, 2015), is widely considered to underpin the development of the diseases associated with the obese state.…”

Adipose Tissue as an Endocrine Organ

“…Conversely, blockade of Metrnl actions in vivo significantly attenuates chronic cold-exposure-induced alternative macrophage activation and thermogenic reprogramming [70]. Although other studies also suggest that ILC2 cell-derived factors, including interleukin 5 and interleukin 13, act upstream of eosinophil-M2 macrophage cascade during cold-induced adipose browning [71,72], either the number of ILC2, or its stimulating factor IL33, were not found to be significantly altered by cold stimulation, though they are remarkably decreased in obese conditions [71,72]. This suggests that there exist other physiological cues that entitle the type 2 immune response during cold adaptation.…”