Activated Type 2 Innate Lymphoid Cells Regulate Beige Fat Biogenesis

Abstract

SUMMARY Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2-and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα+ APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis.

Caloric Restriction Leads to Browning of White Adipose Tissue through Type 2 Immune Signaling

“…These results demonstrate that the increased type 2 signaling and the innate immunity are of key importance for a number of metabolic improvements during CR. In contrast to the cold exposure (Lee et al, 2015), CR did not affect the levels of the ILC2 cells, suggesting alternative upstream mechanisms contributing to the increased eosinophil and M2 levels.…”

“…While no changes were detected in the corticosterone levels (Figures S4A and S4B), the type 2 cytokines IL-4, IL-5, and IL-13 were markedly upregulated in both ingSAT and pgVAT of CR mice compared to the AL controls ( Figures 4A, S4C, and S4D). Eosinophils and the type 2 cytokines are sufficient to promote beige fat development through alternative activation of M2 macrophages expressing tyrosine hydroxylase (TH) (Ganeshan and Chawla, 2014;Lee et al, 2015;Martinez et al, 2009;Qiu et al, 2014), rate-limiting enzyme in the catecholamine biosynthesis (Nguyen et al, 2011). Indeed, Th mRNA and TH protein levels were increased in ingSAT and pgVAT in the CR mice ( Figures 4B and S4E).…”

“…), both models showing impaired type 2 cytokine signaling (Lee et al, 2015;Qiu et al, 2014). The Il4ra À/À animals and their respective controls were on a BALB/c background, while the Stat6 À/À mice were on a C57BL/6J background.…”

Continuous cold exposure induces an anti-inflammatory response in mesenteric adipose tissue associated with catecholamine production and thermogenin expression in rats

“…Th e mechanisms include secretion of IL-4 by eosinophils, which stimulate an alternative activation of macrophages and their catecholamine (CA) production (Nguyen et al 2011;Qiu et al 2014), and the activation of type 2 innate lymphoid cells by IL-33, leading to proliferation of the bipotential adipocyte precursors and their subsequent commitment to the beige fat lineage (Lee et al 2015).…”

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.…”