Marked IL-35+ cell accumulation was observed in the adipose tissues, gut tissues and other organs (e.g., spleen) of huREG4IECtg mice, which were resistant to HFD-mediated obesity, whereas fewer IL-35+ cells were observed in Reg4 KO mice than in their control WT littermates. Here, REG4 is linked to obesity due to melanocortin 4 receptor deficiency.