Abstract

Introduction: Beige adipocytes hold therapeutic promise for obese and diabetic patients. Beige adipocytes can be generated from tissue-residing beige progenitors (APCs) in response to cold temperatures preferably around lymph nodes (LN), suggesting that there are unique LN-derived signals controlling beige adipocyte generation. Methods: CCR4 KO mice (spCas9 mice were injected with AAV8-CCR4-sgRNA into biolateral inguinal adipose tissue) were generated on a C57BL/6 background. Stromal vascular cells were isolated and differentiated into beige adipocytes for in vitro studies. Flow cytometer analysis were conducted for sorting and identifying immune cells. Results: Here, we show that local LN removal greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived chemokine C-C motif ligand 22 (CCL22) into iWAT. Mechanistically, cold exposure increases the level of CCL22, which binds to its receptor C-C chemokine motif receptor 4 (CCR4), and then promotes beiging. Furthermore, CCL22 levels are inversely correlated with body weight and fat mass, and elevated CCL22 levels prevent diet-induced obesity along with increased energy expenditure in mice and humans. Conclusion: The results suggest that beige adipogenesis around the inguinal LNs of white adipose tissues depends on the CCL22-CCR4 signaling. Our findings underline the potential of targeting the CCL22-CCR4 axis to counter obesity and its associated health complications.