Objective: Insulin resistance (IR) is based on chronic inflammation in part through the activation of adipose tissue macrophages (Mϕ). Nonalcoholic fatty liver disease (NAFLD) is accepted to be strongly associated with IR. Mϕ in adipose tissue and liver have been reported to proliferate, but the pathophysiological significance of tissue Mϕ proliferation remains unclear. We examined the effects of Mϕ proliferation on IR and tissue inflammation using high-fat fed mice whose Mϕ proliferation was specifically inhibited.

Methods and Results: Mϕ specific inhibition of proliferation in mice was achieved by transgenic expression of cyclin-dependent kinase inhibitor 1B (p27kip) under the regulation of scavenger receptor promoter/enhancer. After 10-week high-fat diet load in control and Tg mice, glucose tolerance and IR were assessed, and liver and epididymal white adipose tissue (eWAT) were collected. Significant improvement of IR was showed in Tg mice in ipGTT, ipITT, ipPTT, and tissue Akt phosphorylation after insulin injection. Increased peripheral insulin sensitivity and reduced hepatic glucose production in Tg mice were confirmed by glucose clump. In Immunohistochemistry, proliferation of Mϕ was suppressed in liver and eWAT from Tg mice. Liver triglyceride content decreased in Tg mice. The mRNA expression of M1 Mϕ markers were decreased, and that of M2 Mϕ markers were increased in liver and eWAT of Tg mice. Crown-like structure formation was less observed in Tg eWAT. The mRNA expression of inflammatory cytokines/chemokines was suppressed, and that of M2 Mϕ marker was increased in Tg eWAT. Flow cytometry analysis confirmed decreased M1/​​M2 ratio in liver and eWAT Mϕ from Tg mice.

Conclusions: Proliferation of Mϕ is involved in the development of IR in liver and adipose tissue, and the progression of hepatic steatosis. Inhibition of Mϕ proliferation ameliorates tissue inflammation, therefore could potentially be the therapeutic target for IR and type 2 diabetes.


T. Wada: None. T. Senokuchi: None. S. Yamada: None. Y. Morita: None. H. Motoshima: None. T. Matsumura: None. E. Araki: Advisory Panel; Self; Abbott. Speaker’s Bureau; Self; ARKRAY, Astellas Pharma Inc., AstraZeneca, Eli Lilly Japan K.K., Merck & Co., Inc., Novo Nordisk Inc., WebMD LLC. Other Relationship; Self; Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

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