Innate immune regulation of metabolic homeostasis

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Obesity is an increasingly prevalent disease that increases the risk of developing numerous diseases including type 2 diabetes, hypertension and stroke. Although the pathogenesis of obesity is complex and multifactorial, it is fundamentally caused by chronic positive energy balance. Interleukin (IL)-4, IL-5 and IL-13 are critical regulators of energy expenditure and metabolic homeostasis that are secreted by group 2 innate lymphoid cells (ILC2s) and that are a dominant source of IL-5 and IL-13 in murine white adipose tissue (WAT). ILC2s are reduced in WAT of high fat diet (HFD)-fed obese mice compared to mice fed a control diet and in samples from obese donors compared to lean donors. Mice lacking IL-33, a cytokine that is essential for ILC2 function, gained more weight and exhibited increased adipocytes compared to IL-33-sufficient controls on a HFD. In contrast, administration of exogenous IL-33 markedly increased WAT ILC2s and decreased WAT mass. Adoptive transfer of IL-33 stimulated ILC2s in mice that lack all ILCs led to increased energy expenditure and beiging of WAT. This effect was regulated by expression of prohormone convertase 1 (Pcsk1) in ILC2s that cleaves proenkephalin A (Penk) into biological active methionine-enkephalin that can engage opioid receptors expressed by adipocytes.Collectively, these data demonstrate that the IL-33-WAT-ILC2 axis regulates metabolic homeostasis and the pathogenesis of obesity. However, the mechanism is poorly defined. Therefore, I propose two specific aims to address the following questions:Aim 1: How are ILC2s recruited to WAT and what is their tissue specific expression pattern? Aim 1 is designed to further investigate the phenotype, migration and recruitment of WAT ILC2s in the murine system. In 1A I will assess the phenotypic surface marker expression of ILC2s in the WAT compared to ILC2s from lung and small intestine. In 1B I will detect the whole transcriptome of ILC2s from WAT and test whether tissue-specific location of ILC2s influences their transcriptional profiles. In 1C I will investigate which molecules ILC2s express to migrate to WAT. In 1D I will test which cells in WAT produce IL-33 and how IL-33 expression is regulated. Aim 2: How are ILC2 effector molecules controlled and what are the signaling pathways in adipocytes?In aim 2A I propose to determine the pathways that are differentially regulated in ILC2s from mice that have been fed conventional diet or HFD and from non-obese or obese human donors on whole transcriptome level. In 2B, I will investigate the regulation and function of Pcsk1 and Penk. In 2C, I will adoptively transfer ILC2s from various gene-deficient mice such as Pcsk1-/-, Penk-/-, Il5-/-, Il4r-/-, Tslpr-/- and Il17rb-/- in alymphoid mice to determine essential pathways regulating ILC2 responses in WAT. In 2D, I will investigate the Oprd1 and Prdm16 signaling pathways in adipocytes.