Type 2 responses at the interface between immunity and fat metabolism

Abstract

Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect 'healthy' physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize the literature regarding type 2 immunity's role in adipose tissue physiology and allude to its potential therapeutic implications.

Figure 1. Tissue-resident leukocytes augment beige adipose tissue development and function

Mammals respond to sustained cold stress by increasing SNS input to subcutaneous white adipose tissue (scWAT), which results in commitment of adipocyte precursors to and their subsequent differentiation into beige adipocytes, activation of thermogenic metabolism in those beige adipocytes, and lipolysis in neighboring white adipocytes to fuel metabolic respiration. Due to scWAT’s scant sympathetic innervation, however, SNS input alone is insufficient to drive this program. Instead, SNS stimulation requires augmentation by tissue resident leukocytes in 4 primary ways: 1) ILC2-derived IL-13 and eosinophil-derived IL-4 directly stimulate adipocyte precursor proliferation, 2) ILC2-derived Met-Enk and adipose tissue macrophage (ATM)-derived catecholamines promote beige differentiation, and finally, ATM-derived catecholamines activate 3) beige adipocyte thermogenesis, and 4) white adipocyte lipolysis. Abbreviations not used elsewhere: Eos, eosinophils; NE, catecholamines; FFAs, free fatty acids; Met-Enk, met-enkephalin.