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Obesity Studies

Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance

  1. Yun Sok Lee1,2,3,
  2. Pingping Li3,
  3. Jin Young Huh1,2,
  4. In Jae Hwang1,2,
  5. Min Lu3,
  6. Jong In Kim1,2,
  7. Mira Ham1,2,
  8. Saswata Talukdar3,
  9. Ai Chen3,
  10. Wendell J. Lu3,
  11. Guatam K. Bandyopadhyay3,
  12. Reto Schwendener4,
  13. Jerrold Olefsky3 and
  14. Jae Bum Kim1,2,5⇓
  1. 1Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Korea
  2. 2School of Biological Sciences, Seoul National University, Seoul, Korea
  3. 3Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
  4. 4Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
  5. 50Department of Biophysics and Chemical Biology, Seoul National University, Seoul, Korea
  1. Corresponding author: Jae Bum Kim, jaebkim{at}snu.ac.kr.
  1. Y.S.L., P.L., and J.Y.H. contributed equally to this study.

Diabetes 2011 Oct; 60(10): 2474-2483. https://doi.org/10.2337/db11-0194
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  • FIG. 1.
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    FIG. 1.

    In 3 days of HFD, body weight, fat mass, and adipocyte size are increased significantly. Eight-week-old C57BL6J male mice were fed NCD until they were subjected to 60% HFD. HFD was treated to the mice 0 (NCD), 3 days (3 D), 1 week (1 W), 2 weeks (2 W), 5 weeks (5 W), or 10 weeks (10 W) before death. At the age of 18 weeks, all mice were killed and subjected to several analyses. A: Body weight of the mice at the end of the experiment. n = 8 at each time point. Increase of body weight started to be observed by 3 days of HFD. Body weight of mice with 5-week HFD and 10-week HFD was not significantly different. **P < 0.05. B: Epididymal (Epid.) fat mass. n = 8 at each time point. **P < 0.05; ***P < 0.001. C: Histology analysis of epididymal adipose tissue. The epididymal adipose tissues were subjected to hematoxylin-eosin staining. n = 4 at each time point. D and E: Further qualitative changes of adipocyte size and morphology by short-term HFD were assessed by histology analysis of whole-mount epididymal adipose tissue. D: BODIPY (boron-dipyrromethene) staining of whole-mount adipose tissue from the mice treated with NCD or HFD. Adipocyte size was markedly increased by 3 days of HFD. n = 6. Signal intensity of BODIPY staining was adjusted for optimal measurement of adipocyte size using ImageJ software. E: Distribution of adipocyte size in epididymal adipose tissue from mice treated with NCD or HFD. (A high-quality digital representation of this figure is available in the online issue.)

  • FIG. 2.
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    FIG. 2.

    HFD induces systemic insulin resistance in 3 days. A: C57BL/6J male mice were treated with NCD or HFD and subjected to oral glucose (Glc) tolerance test. n = 8 at each time point. ***P < 0.001 NCD vs. 3-day HFD. B: Blood insulin levels at time 0 and 10 min after glucose injection. Basal insulin level was significantly elevated by 3 days of HFD and then further increase was detected significantly by 5 and 10 weeks of HFD. n = 8. *P < 0.05 NCD vs. 3-day HFD; ***P < 0.001 NCD vs. 3-day HFD; †P < 0.05 3-day HFD vs. 10-week HFD; ††P < 0.01 3-day HFD vs. 10-week HFD. C–H: Hyperinsulinemic-euglycemic clamp was performed in mice treated with HFD for different periods; n = 8 (NCD, and 3-day and 1-week HFD mice) or n = 6 (10-week HFD mice). C: Basal blood glucose level (before clamp). **P < 0.01. D: Basal hepatic glucose production. *P < 0.05; **P < 0.01. E: GIR. **P < 0.01. F: ISGDR. **P < 0.01. G: Insulin-dependent suppression of hepatic glucose. **P < 0.01. H: Suppression of plasma FFA level by insulin. *P < 0.05; **P < 0.01.

  • FIG. 3.
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    FIG. 3.

    Macrophage (MP) infiltration and polarization increase in 3 days of HFD. Mice were treated with NCD (N) or HFD for a series of periods as indicated: 3D, 3 days; 2W, 2 weeks; 10W, 10 weeks. After 10 weeks from when first mice were fed an HFD, mice were killed and epididymal adipose tissues were taken for further analyses. A: Flow cytometry analyses of immune cells in stromal vascular fraction of adipose tissue. #P < 0.05; ##P < 0.01; ###P < 0.001; n = 4 (NCD and 2-week HFD mice) or n = 6 (1-week and 10-week HFD mice). B: Immunohistochemistry analysis of epididymal adipose tissue. The epididymal adipose tissues were stained with antibodies against MAC2 and then subjected to hematoxylin-eosin staining. n = 4. C: Whole-mount immunohistochemistry analysis of epididymal adipose tissue from NCD or 3- or 7-day HFD-treated mice. Samples were stained with DAPI (blue) or antibodies against CD11b (red) and CD11c (green) and visualized by multiphoton confocal microscopy. Scale bar denotes 50 μm. (A high-quality digital representation of this figure is available in the online issue.)

  • FIG. 4.
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    FIG. 4.

    Inflammatory gene expression is induced in 3 days after HFD. C57BL/6J mice were treated with an HFD. Mice were fed an HFD for 0 (0 or N [NCD]), 1 (1), 3 (3), or 7 days (7), or 16 weeks (H). mRNA levels of inflammatory genes from epididymal adipose tissue (WAT), brown adipose tissue (BAT), liver, and skeletal muscle were measured by quantitative real-time RT-PCR analysis. n = 10 at each time point. *P < 0.05; **P < 0.01; ***P < 0.001. iNOS, inducible nitric oxide synthase; SAA3, serum amyloid A3.

  • FIG. 5.
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    FIG. 5.

    Adipocytes become more chemoattractive to macrophages after 3 days of HFD. A: Macrophage migration assays using primary ACM from mice treated with NCD (N) or HFD. ACM were obtained by incubating mouse primary adipocytes in serum-free Dulbecco’s modified Eagle’s medium for 12 h. 3d, 3 days; 1w, 1 week. B: MCP-1 protein expression from the primary adipocytes. C: MCP-1 protein secretion from those adipocytes. *P < 0.05; **P < 0.01.

  • FIG. 6.
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    FIG. 6.

    Rag1 KO mice develop insulin resistance with increased macrophage activation in 1 week of HFD. A: Macrophage infiltration and M1 polarization were increased by short-term HFD. Rag1 KO mice were treated with HFD for 1 week and killed, and epididymal adipose tissues were taken for further analyses. Total macrophages (double positive; F4/80+, CD11b+) and CD11c+ macrophages (triple positive cells; F4/80+, CD11b+, CD11c+) were increased in adipose tissue in 1 week of HFD. *P < 0.05 KO-NCD vs. KO HFD; ***P < 0.001 KO-NCD vs. KO HFD; #P < 0.05 wild-type (WT)-NCD vs. WT HFD; ##P < 0.01 WT-NCD vs. WT HFD. n = 6. B: Epididymal (Epid.) adipose tissue mass in NCD and 1-week HFD-treated Rag1 KO mice. C: Expression of inflammatory genes was promoted in 1-week HFD-fed Rag1 KO mice. mRNA levels of inflammatory genes from epididymal adipose tissue were measured by quantitative real-time RT-PCR analysis. D–F: HFD rapidly induces systemic insulin resistance in Rag1 KO mice. D: Rag1 KO mice (8 weeks old, male) were treated with NCD or HFD for 3 days (3d) (i) or 1 week (1w) (ii) and subjected to oral glucose (Glc) tolerance test. E: Serum insulin levels of Rag1 KO mice treated with NCD or HFD (for 1 week) during oral glucose tolerance. 0 min, before glucose injection; 10 min, 10 min after glucose injection. F: WT or Rag1 KO mice were treated with NCD or HFD for 1 week and subjected to insulin tolerance test with intraperitoneal injection of insulin (IP-ITT). Blood glucose levels were measured at 0, 30, 60, 90, and 120 min after insulin (0.4 unit/kg) injection. G: Glucose-uptake assays using primary adipocytes from mice treated with NCD or HFD for 1 week. iNOS, inducible nitric oxide synthase; SAA3, serum amyloid A3. *P < 0.05; **P < 0.01; ***P < 0.001.

  • FIG. 7.
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    FIG. 7.

    Macrophage depletion using clodronate-liposomes does not affect short-term HFD-dependent adipocyte insulin resistance. Mice were treated with NCD or 60% HFD in the presence or absence of clodronate injection. Mice were given clodronate injection (100 mg/kg i.p.) 3 days before HFD, which was followed by a second and third injection every 3 days (at days 0 and 3). A: Flow cytometry analysis of CD11c+ macrophages in adipose tissue. V, vehicle (empty liposomes); C, clodronate-liposomes. B: Whole-mount immunohistochemistry analysis of epididymal adipose tissue. Veh, vehicle; Clod, clodronate-liposomes. C: Cytokine concentration in the mouse sera injected with vehicle and clodronate. W, week. *P < 0.05. D: Glucose-uptake assays using primary adipocytes from mice treated with NCD or HFD for 1 week with or without clodronate injection. White columns denote relative glucose uptake activity without insulin. Black columns denote relative glucose uptake activity with insulin. Cld, clodronate-liposomes. E: Oral glucose tolerance test (OGTT) of mice treated with HFD for 3 days. #P < 0.05 Veh-NCD vs. Veh-HFD; *P < 0.05 Cld-NCD vs. Cld-HFD; **P < 0.01 Cld-NCD vs. Cld-HFD; ***P < 0.001 Cld-NCD vs. Cld-HFD. n = 6. F: Glucose tolerance test of mice treated with HFD for 7 days. #P < 0.05 Veh-NCD vs. Veh-HFD; ##P < 0.01 Veh-NCD vs. Veh-HFD; ###P < 0.001 Veh-NCD vs. Veh-HFD; *P < 0.05 Cld-NCD vs. Cld-HFD; **P < 0.01 Cld-NCD vs. Cld-HFD. n = 6. G: Homeostasis model assessment of insulin resistance (HOMA-IR). H–J: Hematopoietic cell-specific JNK deficiency does not affect short-term HFD-induced insulin resistance. For the generation of radiation chimera, C57BL/6J mice received a lethal dose of 10 Gy of ionizing radiation, followed by tail vein injection of 107 bone marrow cells either from wild-type (WT) or JNK KO mice. After 6 weeks of bone marrow reconstitution, mice were subjected to 3 or 7 days of HFD, followed by hyperinsulinemic-euglycemic clamp. n = 4 to 5. H: GIR. I: ISGDR. J: Insulin-dependent hepatic glucose suppression. BMT, bone marrow transplantation. (A high-quality digital representation of this figure is available in the online issue.)

  • FIG. 8.
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    FIG. 8.

    Lipid contents of liver and skeletal muscle after 3 days of HFD. Eighteen-week-old C57BL6J male chow-fed mice were started in 60% HFD at day 0 for 3 days before the analyses. A separate group of age-matched chow-fed mice was studied as controls. For the macrophage depletion experiment, two shots of clodronate injection (100 mg/kg i.p.) were given at day −3 and 0. Veh, vehicle; Clod, clodronate-liposomes; TG, triacylglyceride; NS, not significant. A: Lipid contents in liver. B: Lipid contents in skeletal muscle. n = 8. *P < 0.05; **P < 0.01.

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Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance
Yun Sok Lee, Pingping Li, Jin Young Huh, In Jae Hwang, Min Lu, Jong In Kim, Mira Ham, Saswata Talukdar, Ai Chen, Wendell J. Lu, Guatam K. Bandyopadhyay, Reto Schwendener, Jerrold Olefsky, Jae Bum Kim
Diabetes Oct 2011, 60 (10) 2474-2483; DOI: 10.2337/db11-0194

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Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance
Yun Sok Lee, Pingping Li, Jin Young Huh, In Jae Hwang, Min Lu, Jong In Kim, Mira Ham, Saswata Talukdar, Ai Chen, Wendell J. Lu, Guatam K. Bandyopadhyay, Reto Schwendener, Jerrold Olefsky, Jae Bum Kim
Diabetes Oct 2011, 60 (10) 2474-2483; DOI: 10.2337/db11-0194
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