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We further determin the specific involvement of CD206 + M2-like macrophages in terms of insulin sensitivity and adipose tissue remodeling both under normal chow (NC) and high-fat diet (HFD)-fed conditions. We show that CD206 + M2-like macrophages have pivotal roles in WAT remodeling by modulating APs proliferation and differentiation into adipocytes through TGFβ signaling, providing a niche for APs. In the current study, we have successfully performed partial but specific depletion of CD206 + M2-like macrophages without affecting either the number or functions of M1 macrophages, and without affecting body weights or overall adiposity. We hypothesized that M2-like macrophages might be involved in the regulation of remodeling of WAT via TGFβ signaling. Adipose tissues of obese mice and humans showed higher TGFβ1 expression 14, 15, 16. WAT-derived TGFβ1 reportedly contributes to insulin sensitivity, while blockade of TGFβ/smad 3 signaling induces browning to protect against obesity and diabetes 13. TGFβ is often secreted by niche cells, thereby inducing hibernation of tissue stem cells such as hematopoietic and melanocyte stem cells 11, 12. TGFβ and related factors control the development, growth and function of diverse cell types. M2 macrophages are required for maintenance of homeostasis, tissue remodeling, and metabolic adaptation under nutrient surplus conditions 9, 10, but it is largely unknown how macrophages participate in progenitor activation and adipogenesis. Obesity is associated with a phenotypic transformation of macrophages, from anti-inflammatory M2 to pro-inflammatory M1 macrophages, thereby causing insulin resistance 1, 7, 8. It is still unknown how the proliferation and differentiation of APs are regulated by M2-like macrophages within WAT, thus controlling the insulin sensitivity.
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Several groups, including our laboratory, have reported that M1-like inflammatory macrophages regulate the expression of angiogenic genes in preadipocytes 3, 6, suggesting interactions between macrophages and APs. However, the cellular and molecular mechanisms regulating adipocyte size and number in vivo are largely unknown.
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Adipocyte size is inversely related to insulin resistance 5, whereas the number of adipocytes is related to the pool size of adipocyte progenitors (APs). The WAT expansion greatly affects the pathogenesis of obesity through different cellular mechanisms 4. White adipose tissue (WAT) markedly adapts to nutrient excess through adipocyte hypertrophy and hyperplasia 1, 2, 3. Our findings indicate that CD206 + M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity. Mice genetically engineered to have reduced numbers of CD206 + M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. We show that adipose tissue CD206 + cells are primarily M2-like macrophages, and ablation of CD206 + M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory cytokines.