Several pieces of evidence indicate that Wnt/β-catenin pathway may regulate the mesenchymal stem cells fate proliferation in vivo. The Wnt signaling is also known to inhibit preadipocyte differentiation into adipocyte. Adipose tissue macrophages play important roles in the maintenance of tissue homeostasis by regulating insulin sensitivity via their anti-inflammatory actions. However, how CD206 M2-like macrophages linked to Wnt signaling in maintaining the preadipocyte differentiation, remains elusive. In the present study, we aimed to investigate the physiological role of CD206 linked to Wnt signaling in preadipocyte differentiation. We show that C1q, which can mediate Wnt signaling, is abundantly expressed in CD206 M2-like macrophages in epididymal adipose tissue. Then, we examined whether CD206 M2-macrophages depletion activate or inhibit Wnt signaling and preadipocyte differentiation. Here, we show that the expression of M2 marker genes was reduced with a reduced expression of Wnt signaling genes in adipose tissue of CD206-reduced mice. Western blot analysis confirmed reduced protein level of β-catenin in CD206-reduced mice that can contribute to regulate the preadipocyte/progenitor’s activity. We presumed that the reduction of C1q-induced Wnt signaling promoted adipogenesis. We also found that depletion of CD206 M2-like macrophages resulted in the generation of the smaller adipocyte, upregulated expression of metabolically favorable genes and enhanced insulin sensitivity in both chow and high-fat diet-fed CD206-reduced mice. Taken together, we show that partial depletion of CD206 M2-like macrophages inhibits Wnt/β-catenin pathway activity in mice and increases preadipocyte differentiation, thus ameliorating insulin resistance in lean and obese mice. Disclosure A. Nawaz: Research Support; Spouse/Partner; Astellas Pharma Inc., Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company. Research Support; Self; Japan Society for the Promotion of Science. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Shionogi & Co., Ltd., Takeda Pharmaceutical Company Limited. T. Nakagawa: None. K. Yagi: None. S. Fujisaka: None. K. Tobe: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Japan Diabetes Society. Research Support; Self; Bristol-Myers Squibb Company. K. Okabe: None. T. Kado: None. J. Liu: None. M. Bilal: None. Funding Japan Society for the Promotion of Science