1669-P: The CCL22/CCR4 Axis Promotes Beige Adipocyte Formation by Recruiting Eosinophils

Beige adipocytes hold therapeutic promise for obese and diabetic patients. Thus, there is a clear basic and clinical need to understand the underlying mechanisms for beige adipocyte generation. Beige adipocytes can be generated from tissue-residing beige progenitors (APCs) in response to cold temperatures preferably around lymph nodes (LNs), suggesting that there are unique LN-derived signals controlling beige adipocyte generation. However, the importance of this unique anatomical location remains poorly understood. 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). CCR4 then recruits eosinophils into iWAT and promotes beiging via FAK/p65 signaling. 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. Taken together, our findings reveal that the CCL22-CCR4 axis mediates signals from local LNs to control adipose beiging and energy expenditure, and that this mechanism provides a potential means to mitigate the development of obesity and its complications.