Back
 Health  Vol.9 No.12 , November 2017
Does Obesity without Hyperglycemia Delay Wound Healing in an Obese Mouse Model Induced by a High-Fat Diet?
Abstract: It was unclear that wound healing was delayed in obesity without hyperglycemia. The purpose of this study was to compare the wound healing process between obese and non-obese mice without hyperglycemia by attaching a splint. Three-week-old male mice (C57BL/6N) were fed high-fat diets (60% of calories from fat) in the obesity group, and commercial diets in the control group for 15 weeks. Two circular (4 mm in diameter) full-thickness wounds were made on the dorsal skin. Body weights and serum leptin levels were significantly higher in the obesity group than in the control group until day 15 after wounding. Fasting blood glucose levels before wounding were lower in the obesity group than in a hyperglycemic rodent model. The macrophage infiltration into subcutaneous fat before wounding in the obesity group was negligible. The ratios of the wound area were not significantly different between the two groups. No significant differences were observed in the number of neutrophils or macrophages or new blood vessels and ratio of myofibroblasts or collagen fibers between the two groups. Our results demonstrated that cutaneous wound healing was not delayed in the obesity group without hyperglycemia and macrophage infiltration into the subcutaneous fat and with high serum leptin levels.
Cite this paper: Urai, T. , Nakajima, Y. , Mukai, K. , Asano, K. , Okuwa, M. , Sugama, J. and Nakatani, T. (2017) Does Obesity without Hyperglycemia Delay Wound Healing in an Obese Mouse Model Induced by a High-Fat Diet?. Health, 9, 1660-1679. doi: 10.4236/health.2017.912122.
References

[1]   Kanazawa, M., Yoshiike, N., Osaka, T., Numba, Y., Zimmet, P. and Inoue, S. (2002) Criteria and Classification of Obesity in Japan and Asia-Oceania. Asia Pacific Journal of Clinical Nutrition, 11, 732S-737S.
https://doi.org/10.1046/j.1440-6047.11.s8.19.x

[2]   Examination Committee of Criteria for “Obesity Disease” in Japan; Japan Society for the Study of Obesity. (2002) New Criteria for “Obesity Disease” in Japan. Circulation Journal, 66, 987-992.

[3]   Guo, S. and Dipietro, L.A. (2010) Factors Affecting Wound Healing. Journal of Dental Research, 89, 219-229.
https://doi.org/10.1177/0022034509359125

[4]   Armstrong, M. (1998) Obesity as an Intrinsic Factor Affecting Wound Healing. Journal of Wound Care, 7, 220-221.
https://doi.org/10.12968/jowc.1998.7.5.220

[5]   Wilson, J.A. and Clark, J.J. (2004) Obesity: Impediment to Postsurgical Wound Healing. Advances in Skin & Wound Care, 17, 426-435.
https://doi.org/10.1097/00129334-200410000-00013

[6]   Anaya, D.A. and Dellinger, E.P. (2006) The Obese Surgical Patient: A Susceptible Host for Infection. Surgical Infections (Larchmt), 7, 473-480.
https://doi.org/10.1089/sur.2006.7.473

[7]   Sugerman, H., Windsor, A., Bessos, M. and Wolfe, L. (1997) Intra-Abdominal Pressure, Sagittal Abdominal Diameter and Obesity Comorbidity. Journal of Internal Medicine, 241, 71-79.
https://doi.org/10.1046/j.1365-2796.1997.89104000.x

[8]   Kabon, B., Nagele, A., Reddy, D., Eagon, C., Fleshman, J.W., Sessler, D.I. and Kurz, A. (2004) Obesity Decreases Perioperative Tissue Oxygenation. Anesthesiology, 100, 274-280.
https://doi.org/10.1097/00000542-200402000-00015

[9]   Urai, T., Haryanto, Mukai, K., Matsushita, T., Asano, K., Nakajima, Y., Okuwa, M., Sugama, J. and Nakatani, T. (2016) The Relationship between Cutaneous Wounds Made on Obese Mice or Those with Decreased Body Weight and Serum Leptin Level. Health, 8, 1015-1028.
https://doi.org/10.4236/health.2016.811105

[10]   Urai, T., Asano, K., Nakajima, Y., Mukai, K. and Nakatani, T. (2017) Effectiveness of Using an Ostomy Skin Barrier/wafer as a Splint to Maintain the Shapes of Circular Cutaneous Wounds in Obese Mice. Structure and Function, 15, 57-61. (In Japanese with English Ab-stract)

[11]   Abranches, M.V., de Oliveira, F.C.E., da Conceicao, L.L. and Peluzio, M.do.C.G. (2015) Obesity and Diabetes: The Link between Adipose Tissue Dysfunction and Glucose Homeostasis. Nutrition Research Reviews, 28, 121-132.
https://doi.org/10.1017/S0954422415000098

[12]   Suganami, T. and Ogawa, Y. (2010) Adipose Tissue Macrophages: Their Role in Adipose Tissue Remodeling. Journal of Leukocyte Biology, 88, 33-39.
https://doi.org/10.1189/jlb.0210072

[13]   Suganami, T., Nishida, J. and Ogawa, Y. (2005) A Paracrine Loop between Adipocytes and Macrophages Aggravates Inflammatory Changes: Role of Free Fatty Acids and Tumor Necrosis Factor α. Arteriosclero-sis, Thrombosis, and Vascular Biology, 25, 2062-2068.
https://doi.org/10.1161/01.ATV.0000183883.72263.13

[14]   Schenk, S., Saberi, M. and Olefsky, J.M. (2008) Insulin Sensitivity: Modulation by Nutrients and Inflammation. The Journal of Clinical Investigation, 118, 2992-3002.
https://doi.org/10.1172/JCI34260

[15]   Wajchenberg, B.L. (2000) Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome. Endocrine Reviews, 21, 697-738.
https://doi.org/10.1210/edrv.21.6.0415

[16]   Cottam, D.R., Mattar, S.G., Barinas-Mitchell, E., Eid, G., Kuller, L., Kelley, D.E. and Schauer, P.R. (2004) The Chronic Inflammatory Hypothesis for the Morbidity Associated with Morbid Obesity: Implications and Effects of Weight Loss. Obesity Surgery, 14, 589-600.
https://doi.org/10.1381/096089204323093345

[17]   Sun, K., Kusminski, C.M. and Scherer, P.E. (2011) Adipose Tissue Remodeling and Obesity. The Journal of Clinical Investigation, 121, 2094-2101.
https://doi.org/10.1172/JCI45887

[18]   Rivera-Gonzalez, G., Shook, B. and Horsley, V. (2014) Adipocytes in Skin Health and Disease. Cold Spring Harbor Perspectives in Medicine, 4, a015271.

[19]   Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova, O., Vinson, C., Reitman, M.L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y., Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P. and Kadowaki, T. (2001) The Fat-Derived Hormone Adiponectin Reverses Insulin Resistance Associated with Both Lipoatrophy and Obesity. Nature Medicine, 7, 941-946.
https://doi.org/10.1038/90984

[20]   Awazawa, M., Ueki, K., Inabe, K., Yamauchi, T., Kubota, N., Kaneko, K., Kobayashi, M., Iwane, A., Sasako, T., Okazaki, Y., Ohsugi, M., Takamoto, I., Yamashita, S., Asahara, H., Akira, S., Kasuga, M. and Kadowaki, T. (2011) Adiponectin Enhances Insulin Sensitivity by Increasing Hepatic IRS-2 Expression via a Macro-phage-Derived IL-6-Dependent Pathway. Cell Metabolism, 13, 401-412.
https://doi.org/10.1016/j.cmet.2011.02.010

[21]   Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K. and Kasuga, M. (2006) MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity. The Journal of Clinical Investigation, 116, 1494-1505.
https://doi.org/10.1172/JCI26498

[22]   Liu, C., Feng, X., Li, Q., Wang, Y., Li, Q. and Hua, M. (2016) Adiponectin, TNF-α and Inflammatory Cytokines and Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis. Cytokine, 86, 100-109.
https://doi.org/10.1016/j.cyto.2016.06.028

[23]   Yoshiike, N., Nishi, N., Matsushima, S., Itou, C., Ikeda, Y., Kashihara, H., Yoshinaga, H., Ogura, H., Komine, S., Satou, Y., Satoh, N., Sasaki, A., Fujioka, S., Oku, J., Amemiya, S., Sakata, T. and Inoue, S. (2000) Relation between Body Mass Index and Risk for Diabetes, Hypertension, Hyperlipidemia—An Epidemiological Study by Multicenter Cooperative Study. HimanKenkyu, 6, 4-17. (In Japanese)

[24]   Jerant, A., Bertakis, K.D. and Franks, P. (2015) Body Mass Index and Health Care Utilization in Diabetic and Nondiabetic Individuals. Medical Care, 53, 409-416.
https://doi.org/10.1097/MLR.0000000000000343

[25]   Goodson, W.H. and Hunt, T.K. (1986) Wound Collagen Accumulation in Obese Hyperglycemic Mice. Diabetes, 35, 491-495.
https://doi.org/10.2337/diab.35.4.491

[26]   Huang, L., Nakagami, G., Minematsu, T., Kinoshita, A., Sugama, J., Nakatani, T., Sagara, H. and Sanada, H. (2010) Ulceration and Delayed Healing Following Pressure Loading in Hyperglycemic Rats with an Immature Dermal Collagen Fiber Network. Wounds, 22, 237-244.

[27]   Ingalls, A.M., Dickie, M.M. and Snell, G. (1950) Obese, a New Mutation in the House Mouse. Journal of Heredity, 41, 317-318.
https://doi.org/10.1093/oxfordjournals.jhered.a106073

[28]   Hummel, K.P., Dickie, M.M. and Coleman, D.L. (1966) Diabetes, a New Mutation in the Mouse. Science, 153, 1127-1128.
https://doi.org/10.1126/science.153.3740.1127

[29]   Jetten, N., Roumans, N., Gijbels, M.J., Romano, A., Post, M.J., De Winther, M.P.J., Van Der Hulst, R.R.W.J. and Xanthoulea, S. (2014) Wound Administration of M2-Polarized Macrophages Does Not Improve Murine Cutaneous Healing Responses. PLoS ONE, 9, e102994.
https://doi.org/10.1371/journal.pone.0102994

[30]   Brown, D.L., Kao, W.W.Y. and Greenhalgh, D.G. (1997) Apoptosis Down-Regulates Inflammation under the Advancing Epithelial Wound Edge: Delayed Patterns in Diabetes and Improvement with Topical Growth Factors. Surgery, 121, 372-380.
https://doi.org/10.1016/S0039-6060(97)90306-8

[31]   Seitz, O., Schurmann, C., Hermes, N., Muller, E., Pfeilschifter, J., Frank, S. and Goren, I. (2010) Wound Healing in Mice with High-Fat Diet- or ob Gene-Induced Diabetes-Obesity Syndromes: A Comparative Study. Experimental Diabetes Research, 2010, Article ID: 476969.

[32]   Cefalu, W.T. (2006) Animal Models of Type 2 Diabetes: Clinical Presentation and Pathophysiological Relevance to the Human Condition. ILAR Journal, 47, 186-198.
https://doi.org/10.1093/ilar.47.3.186

[33]   Rees, D.A. and Alcolado, J.C. (2005) Animal Models of Diabetes Mellitus. Diabetic Medicine, 22, 359-370.
https://doi.org/10.1111/j.1464-5491.2005.01499.x

[34]   Nascimento, A.P. and Costa, A.M. (2006) Overweight Induced by High-Fat Diet Delays Rat Cutaneous Wound Healing. British Journal of Nutrition, 96, 1069-1077.
https://doi.org/10.1017/BJN20061955

[35]   Nascimento, A.P. and Costa, A.M. (2011) Both Obesity-Prone and Obesity-Resistant Rats Present Delayed Cutaneous Wound Healing. British Journal of Nutrition, 106, 603-611.
https://doi.org/10.1017/S0007114511000468

[36]   Nakajima, Y., Nakano, Y., Fuwano, S., Hayashi, N., Hiratoko, Y., Kinoshita, A., Miyahara, M., Mochizuki, T., Nishino, K., Tsuruhara, Y., Yokokawa, Y., Iuchi, T., Kon, Y., Mukai, K., Kitayama, Y., Murakado, N., Okuwa, M. and Nakatani, T. (2013) Effects of Three Types of Japanese Honey on Full-Thickness Wound in Mice. Evidence-Based Complementary and Alternative Medicine, 2013, Article ID: 504537. https://doi.org/10.1155/2013/504537

[37]   Mukai, K., Koike, M., Nakamura, S., Kawaguchi, Y., Katagiri, F., Nojiri, S., Yamada, Y., Miyajima, E., Matsumoto, M., Komatsu, E., Nakajima, Y., Urai, T., Murakado, N. and Nakatani, T. (2015) Evaluation of the Effects of a Combination of Japanese Honey and Hydrocolloid Dressing on Cutaneous Wound Healing in Male Mice. Evidence-Based Complementary and Alternative Medicine, 2015, Article ID: 910605. https://doi.org/10.1155/2015/910605

[38]   Elgazar-Carmon, V., Rudich, A., Hadad, N. and Levy, R. (2008) Neutrophils Transiently Infiltrate Intra-Abdominal Fat Early in the Course of High-Fat Feeding. The Journal of Lipid Research, 49, 1894-1903.
https://doi.org/10.1194/jlr.M800132-JLR200

[39]   Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L. and Ferrante, A.W. (2003) Obesity Is Associated with Macrophage Accumulation in Adipose Tissue. The Journal of Clinical Investigation, 112, 1796-1808.
https://doi.org/10.1172/JCI200319246

[40]   Ito, A., Suganami, T., Miyamoto, Y., Yoshimasa, Y., Takeya, M., Kamei, Y. and Ogawa, Y. (2007) Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy. The Journal of Biological Chemistry, 282, 25445-25452.
https://doi.org/10.1074/jbc.M701549200

[41]   Frank, S., Stallmeyer, B., Kampfer, H., Kolb, N. and Pfeilschifter, J. (2000) Leptin Enhances Wound Re-Epithelialization and Constitutes a Direct Function of Leptin in Skin Repair. The Journal of Clinical Investigation, 106, 501-509.
https://doi.org/10.1172/JCI9148

[42]   Tadokoro, S., Ide, S., Tokuyama, R., Umeki, H., Tatehara, S., Kataoka, S., Satomura, K. (2015) Leptin Promotes Wound Healing in the Skin. PLoS ONE, 10, e0121242.
https://doi.org/10.1371/journal.pone.0121242

[43]   Murad, A., Nath, A.K., Cha, S.T., Demir, E., Flores-Riveros, J. and Sierra-Honigmann, M.R. (2003) Leptin Is an Autocrine/Paracrine Regulator of Wound Healing. The FASEB Journal, 17, 1895-1897.
https://doi.org/10.1096/fj.03-0068fje

[44]   Ezure, T. and Amano, S. (2007) Adiponectin and Leptin Up-Regulate Extracellular Matrix Production by Dermal Fibroblasts. Biofactors, 31, 229-236.
https://doi.org/10.1002/biof.5520310310

[45]   Martyn, J.A.J., Kaneki, M. and Yasuhara, S. (2008) Obesity-Induced Insulin Resistance and Hyperglycemia: Etiologic Factors and Molecular Mechanisms. Anesthesiology, 109, 137-148.
https://doi.org/10.1097/ALN.0b013e3181799d45

[46]   Chan, J.M., Rimm, E.B., Colditz, G.A., Stampfer, M.J. and Willett, W.C. (1994) Obesity, Fat Distribution, and Weight Gain as Risk Factors for Clinical Diabetes in Men. Diabetes Care, 17, 961-969.
https://doi.org/10.2337/diacare.17.9.961

[47]   Colditz, G.A., Willett, W.C., Rotnitzky, A. and Manson, J.E. (1995) Weight Gain as a Risk Factor for Clinical Diabetes Mellitus in Women. Annals of Internal Medicine, 122, 481-486.
https://doi.org/10.7326/0003-4819-122-7-199504010-00001

[48]   Goto, Y., Kakizaki, M. and Masaki, N. (1976) Production of Spontaneous Diabetic Rats by Repetition of Selective Breeding. The Tohoku Journal of Experimental Medicine, 119, 85-90.
https://doi.org/10.1620/tjem.119.85

[49]   Broughton II, G., Janis, J.E. and Attinger, C.E. (2006) The Basic Science of Wound Healing. Plastic and Reconstructive Surgery, 117, 12S-34S.
https://doi.org/10.1097/01.prs.0000225430.42531.c2

 
 
Top