CD11c expression in adipose tissue and blood and its role in diet-induced obesity

Abstract

Objective: To examine CD11c, a beta(2)-integrin, on adipose tissue (AT) leukocytes and blood monocytes and its role in diet-induced obesity.

Methods and results: High-fat diet-induced obese C57BL/6 mice, CD11c-deficient mice, and obese humans were studied. CD11c, leukocytes, and chemokines/cytokines were examined in AT and/or blood by flow cytometry, RNase protection assay, quantitative polymerase chain reaction, or enzyme-linked immunosorbent assay. Obese C57BL/6 mice had increased CD11c in AT and blood compared with lean controls. CD11c messenger RNA positively correlated with monocyte chemoattractant protein 1 in human visceral AT. Obese humans with metabolic syndrome had a higher CD11c level on blood monocytes compared with lean humans. Low-fat diet-induced weight loss reduced blood monocyte CD11c in obese mice and humans. Mouse and human monocyte CD11c levels and mouse AT CD11c messenger RNA correlated with insulin resistance. CD11c deficiency in mice did not alter weight gain but decreased inflammation, evidenced by a lower T-cell number and reduced levels of major histocompatibility complex class II, C-C chemokine ligand 2 (CCL5), CCL4, and interferon gamma in AT, and ameliorated insulin resistance and glucose intolerance associated with diet-induced obesity.

Conclusions: Diet-induced obesity increased CD11c in both AT and blood in mice and humans. CD11c plays an important role in T-cell accumulation and activation in AT, and contributes to insulin resistance associated with obesity.

Figure 1. CD11c expression in mouse AT and blood

A: Representative FACS analysis showing expression of F4/80, CD205, MHC class II (I-A/I-E), and Ly-6C on CD11b⁺/CD11c⁺ and CD11b⁺/CD11c⁻ cells from AT of lean (ND) or obese (HF) male mice. B: CD11b⁺/CD11c⁺ cell numbers in AT of obese (n=9) and lean (n=7) male mice. C: CD11c⁺ and CD11c⁻ monocytes in blood of obese and lean mice, and in obese mice with normal diet–induced weight loss (HF-WL); n=8–10/group.

Figure 1. CD11c expression in mouse AT and blood

A: Representative FACS analysis showing expression of F4/80, CD205, MHC class II (I-A/I-E), and Ly-6C on CD11b⁺/CD11c⁺ and CD11b⁺/CD11c⁻ cells from AT of lean (ND) or obese (HF) male mice. B: CD11b⁺/CD11c⁺ cell numbers in AT of obese (n=9) and lean (n=7) male mice. C: CD11c⁺ and CD11c⁻ monocytes in blood of obese and lean mice, and in obese mice with normal diet–induced weight loss (HF-WL); n=8–10/group.

Figure 2. CD11c, CD11b, and MCP-1 in human AT or blood

A: Correlation of MCP-1 mRNA with CD11c in human VAT as detected by quantitative RT-PCR; n=21. B: Correlation of MCP-1 mRNA with CD11b in human VAT as detected by quantitative RT-PCR; n=21. C: CD11c levels on blood monocytes of obese humans with metabolic syndrome and lean controls, and of obese humans with metabolic syndrome after weight loss (obese-WL) (n=9 for each of obese and lean groups), indicated as mean fluorescence intensity (MFI) by flow cytometry. D: Correlation of monocyte CD11c with HOMA-IR in human subjects; n=26.

Figure 3. Body weight and weight of fat pads of CD11c^−/− and WT mice

A: CD11c^−/− and WT male mice were fed high-fat diet (HFD) or normal diet (ND) ad libitum, and body weight was monitored weekly for 24 weeks. B: Weights of perigonadal fat pads of CD11c^−/− and WT male mice on HFD or ND for 24 weeks. n=12–16/group, NS: not significant.

Figure 4. T cells in AT of CD11c^−/− and WT mice

A: mRNA levels of CD3 and F4/80 in AT of CD11c^−/− and WT mice examined by RPA; n=10/group. B: Total T cells in AT of CD11c^−/− and WT mice examined by FACS analysis; n=8 each for CD11c^−/− and WT mice on HFD, and n=5 each for CD11c^−/− and WT mice on ND. C: IFN-γ mRNA in AT of CD11c^−/− and WT mice on HFD or ND as examined by quantitative RT-PCR; n=12–15/group. NS: not significant.

Figure 5. Macrophages, MHC class II, and chemokines in AT of CD11c^−/− and WT mice

A: Relative ratios of M1 in total macrophages in AT of CD11c^−/− and WT mice examined by FACS; n=5–7/group. B: mRNA levels of MHC class II (H2-Ab1) in AT of CD11c^−/− and WT mice examined by quantitative RT-PCR; n=12–16/group. C: mRNA levels of RANTES, MIP-1β, and MCP-1 in AT of CD11c^−/− and WT mice examined by RPA; n=5-6/group. NS: not significant.

Figure 6. Metabolic parameters of CD11c^−/− and WT mice

A: Fasting plasma levels of glucose and HOMA-IR in CD11c^−/− and WT mice; n=9–15/group. B: Glucose tolerance test (GTT) in CD11c^−/− and WT mice; n=4/group. NS: not significant.