Mast cell promotes obesity by activating microglia in hypothalamus

Yi Zhang ^* Cheng Hu ^* Wen Tian Jinghui Wang Yangyang Zhu Liwei Chen ^*

• Shanghai Diabetes Research Institute, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China

Obesity has emerged as a critical public health concern; however, its pathogenic mechanisms remain intricate. The central nervous system, particularly the hypothalamus, plays an extremely significant role in energy balance. A disruption in the hypothalamic homeostasis can give rise to obesity and related metabolic disorders.In recent years, the influence of intercellular interactions within the hypothalamus on the formation of obesity has garnered escalating attention, yet the precise mechanisms require further discourse. Mast cells are innate immune cells of the organism. Prior research has revealed their close association with the development of obesity, but the specific mechanisms still merit further exploration. Within the central nervous system, mast cells can fulfill certain functions by activating microglia; however, whether mast cells in the hypothalamus impact microglia and subsequently influence metabolic homeostasis remains unknown. Herein, we discovered that high-fat feeding can lead to an increase in mast cells in the arcuate nucleus of the hypothalamus. These mast cells further activate microglia in the arcuate nucleus of the hypothalamus, suppress the activity of POMC neurons, thereby promoting appetite and inhibiting energy expenditure, resulting in the manifestation of obesity. This investigation highlights the regulatory role of mast cells in the hypothalamus in the formation of obesity and offers a novel target for the treatment of obesity and related metabolic diseases.