Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor (IL-22R) attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell-cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.

Obesity refers to a condition where a person has excessive fat accumulation, which can have negative impacts on their health. Managing obesity has typically relied on reducing energy intake and increasing energy use through diets and exercise. For example, intermittent fasting is a diet strategy involving periods of time in a day or week where a person does not eat any food. Research has shown that intermittent fasting may improve the metabolism and increase energy use by enhancing a process known as "beigeing" of white fat tissue. In this process, white fat cells or their precursor cells differentiate into beige fat cells, which can consume excess energy by burning fat. Consequently, understanding how beigeing of white fat cells is activated in intermittent fasting may reveal a promising strategy for tackling obesity and metabolic diseases. Immune cells found in the gut known as innate lymphoid cells (ILCs) may play a role in the metabolic benefits from intermittent fasting. However, the roles of ILCs are complex: some types of ILCs can promote obesity, while others show metabolic benefits through their release of proteins like IL-17 and IL-22, which can help the body to metabolise glucose. To find out if these immune cells play a role in intermittent fasting, Chen, Sun et al. used diet-induced obese mice that had to fast every other day. Intermittent fasting was found to cause a form of ILCs (ILC3s) to release IL-22, which resulted in beigeing of white fat cells in obese mice. Single-cell sequencing techniques of gut immune cells further revealed that intermittent fasting increased forms of signalling in ILC3s and caused ILC3s to interact with other immune cells, such as dendritic cells and macrophages. The findings demonstrate how intermittent fasting causes beigeing of white adipose tissue through ILC3s, revealing mechanisms underpinning the metabolic benefits found from intermittent fasting. More research into this process may help identify new targets for treating obesity.

Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue.

Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by ILC3s and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell‒cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.