Skip to main content

Advertisement

SpringerLink
Log in

Cotton rat (Sigmodon hispidus) develops metabolic disorders associated with visceral adipose inflammation and fatty pancreas without obesity

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Obesity induces metabolic disorders such as type 2 diabetes, hypertension, and cardiovascular diseases and has become a global health concern. Recent studies imply that fat accumulation in nonadipose tissue correlates with metabolic disorders. However, there are no suitable animal models to evaluate this phenomenon. This study investigated the characteristics of metabolic disorders found in cotton rat (Sigmodon hispidus). Blood biochemical examinations revealed that cotton rats, predominantly males, developed hyperinsulinemia, hyperglycemia, and dyslipidemia when fed a normal diet. The islets increased in size through β-cell hyperplasia, which was associated with serum insulin level in both sexes, strongly indicating insulin resistance. In male cotton rats, oxidative stress was observed in β cells, and macrophage infiltration into the visceral white adipose tissue was reported, both of which were associated with serum insulin level without visceral obesity. In contrast, female cotton rats developed hyperinsulinemia without histopathological changes that were reported in males. Adipocytes were found to be accumulated in the pancreas but not in the liver of both sexes during aging. Pancreatic fat accumulation was associated with the serum insulin level only in females. Taken together, cotton rats developed metabolic disorders associated with visceral fat inflammation in the absence of obesity. In addition, pancreatic ectopic fat may also be related to the early stages of these conditions. Thus, the cotton rat may serve as a novel and useful model for metabolic disorders characterized by visceral adipose inflammation and ectopic fat accumulation in the pancreas without obesity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Azazy AA, Chance ML, Devaney E (1997) A time-course study of circulating antigen and parasite-specific antibody in cotton rats infected with Leishmania donovani. Ann Trop Med Parasitol 91:153–162

    Article  CAS  PubMed  Google Scholar 

  • Blanco JC, Boukhvalova MS, Perez DR, Vogel SN, Kajon A (2014) Modeling human respiratory viral infections in the cotton rat (Sigmodon hispidus). J Antivir Antiretrovir 6:40–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bock T, Pakkenberg B, Buschard K (2003) Increased islet volume but unchanged islet number in ob/ob mice. Diabetes 52:1716–1722

    Article  CAS  PubMed  Google Scholar 

  • Boutens L, Stienstra R (2016) Adipose tissue macrophages: going off track during obesity. Diabetologia 59:879–894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Catanzaro R, Cuffari B, Italia A, Marotta F (2016) Exploring the metabolic syndrome: nonalcoholic fatty pancreas disease. World J Gastroenterol 22:7660–7675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dolenšek J, Rupnik MS, Stožer A (2015) Structural similarities and differences between the human and the mouse pancreas. Islets 7:e1024405

    Article  PubMed  PubMed Central  Google Scholar 

  • Faith RE, Montgomery CA, Durfee WJ, Aguilar-Cordova E, Wyde PR (1997) The cotton rat in biomedical research. Lab Anim Sci 47:337–345

    CAS  PubMed  Google Scholar 

  • Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB, Mandarim-de-Lacerda CA (2010) A mouse model of metabolic syndrome: insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr 46:212–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gu D, Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-gamma transgenic mice. Development 118:33–46

    CAS  PubMed  Google Scholar 

  • Ichii O, Nakamura T, Irie T, Kouguchi H, Nakamura D, Nakamura S, Sato S, Yokoyama K, Horino T, Sunden Y, Elewa YH, Kon Y (2016) Female cotton rats (Sigmodon hispidus) develop chronic anemia with renal inflammation and cystic changes. Histochem Cell Biol 146:351–362

    Article  CAS  PubMed  Google Scholar 

  • Ichii O, Nakamura T, Irie T, Kouguchi H, Sotozaki K, Horino T, Sunden Y, Elewa YHA, Kon Y (2018) Close pathological correlations between chronic kidney disease and reproductive organ-associated abnormalities in female cotton rats. Exp Biol Med 243:418–427

    Article  CAS  Google Scholar 

  • Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, Sharma A, Bonner-Weir S (2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A 105:19915–19919

    Article  PubMed  PubMed Central  Google Scholar 

  • Kanda Y, Shimoda M, Hamamoto S, Tawaramoto K, Kawasaki F, Hashiramoto M, Nakashima K, Matsuki M, Kaku K (2010) Molecular mechanism by which pioglitazone preserves pancreatic β-cells in obese diabetic mice: evidence for acute and chronic actions as a PPARγ agonist. Am J Physiol Endocrinol Metab 298:E278–E286

    Article  CAS  PubMed  Google Scholar 

  • Kayamori F, Igarashi K (1994) Effects of dietary nasunin on the serum cholesterol level in rats. Biosci Biotechnol Biochem 58:570–571

    Article  CAS  Google Scholar 

  • Kooptiwut S, Wanchai K, Semprasert N, Srisawat C, Yenchitsomanus PT (2017) Estrogen attenuates AGTR1 expression to reduce pancreatic β-cell death from high glucose. Sci Rep 7:16639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kroeze WK, Tanner CE (1985) Echinococcus multilocularis: responses to infection in cotton rats (Sigmodon hispidus). Int J Parasitol 15:233–238

    Article  CAS  PubMed  Google Scholar 

  • Lanktree MB, Johansen CT, Joy TR, Hegele RA (2010) A translational view of the genetics of lipodystrophy and ectopic fat deposition. Prog Mol Biol Transl Sci 94:159–196

    Article  CAS  PubMed  Google Scholar 

  • Lingvay I, Esser V, Legendre JL, Price AL, Wertz KM, Adams-Huet B, Zhang S, Unger RH, Szczepaniak LS (2009) Noninvasive quantification of pancreatic fat in humans. J Clin Endocrinol Metab 94:4070–4076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda A, Makino N, Tozawa T, Shirahata N, Honda T, Ikeda Y, Sato H, Ito M, Kakizaki Y, Akamatsu M, Ueno Y, Kawata S (2014) Pancreatic fat accumulation, fibrosis, and acinar cell injury in the Zucker diabetic fatty rat fed a chronic high-fat diet. Pancreas 43:735–743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miao Z, Yan S, Wang J, Wang B, Li Y, Xing X, Yuan Y, Meng D, Wang L, Gu J, Zhang S, Li C, Wang CY (2009) Insulin resistance acts as an independent risk factor exacerbating high-purine diet induced renal injury and knee joint gouty lesions. Inflamm Res 58:659–668

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Ichii O, Irie T, Mizoguchi T, Shinohara A, Kouguchi H, Sunden Y, Otsuka-Kanazawa S, Elewa YHA, Koshimoto C, Nagasaki KI, Kon Y (2018) Cotton rats (Sigmodon hispidus) possess pharyngeal pouch remnants originating from different primordia. Histol Histopathol 33:555–565

    CAS  PubMed  Google Scholar 

  • Niewiesk S, Prince G (2002) Diversifying animal models: the use of hispid cotton rats (Sigmodon hispidus) in infectious diseases. Lab Anim 36:357–372

    Article  CAS  PubMed  Google Scholar 

  • Nolte T, Brander-Weber P, Dangler C, Deschl U, Elwell MR, Greaves P, Hailey R, Leach MW, Pandiri AR, Rogers A, Shackelford CC, Spencer A, Tanaka T, Ward JM (2016) Nonproliferative and proliferative lesions of the gastrointestinal tract, pancreas and salivary glands of the rat and mouse. J Toxicol Pathol 29:1S–125S

    Article  PubMed  PubMed Central  Google Scholar 

  • Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P (2009) Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology 150:2109–2117

    Article  CAS  PubMed  Google Scholar 

  • Sattar N, Gill JM (2014) Type 2 diabetes as a disease of ectopic fat? BMC Med 12:123

    Article  PubMed  PubMed Central  Google Scholar 

  • Tajima S, Horiuchi S (1989) Biological reference data book on experimental animals, 1st ed (Japanese). Soft Science, Tokyo

    Google Scholar 

  • Tsuchitani M, Sato J, Kokoshima H (2016) A comparison of the anatomical structure of the pancreas in experimental animals. J Toxicol Pathol 29:147–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tushuizen ME, Bunck MC, Pouwels PJ, Bontemps S, Van Waesberghe JH, Schindhelm RK, Mari A, Heine RJ, Diamant M (2007) Pancreatic fat content and β-cell function in men with and without type 2 diabetes. Diabetes Care 30:2916–2921

    Article  CAS  PubMed  Google Scholar 

  • Waldum HL, Rørvik H, Falkmer S, Kawase S (1999) Neuroendocrine (ECL cell) differentiation of spontaneous gastric carcinomas of cotton rats (Sigmodon hispidus). Lab Anim Sci 49:241–247

    CAS  PubMed  Google Scholar 

  • Wang MY, Grayburn P, Chen S, Ravazzola M, Orci L, Unger RH (2008) Adipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome. Proc Natl Acad Sci U S A 105:6139–6144

    Article  PubMed  PubMed Central  Google Scholar 

  • Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS (2007) Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 129:537–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao L, Herlea-Pana O, Heuser-Baker J, Chen Y, Barlic-Dicen J (2014) Roles of the chemokine system in development of obesity, insulin resistance, and cardiovascular disease. J Immunol Res 181450

Download references

Acknowledgements

We would like to acknowledge Daisuke Nakamura, Saori Nakamura, Shinobu Sato, and Keisuke Yokoyama in Sankyo Labo Service Corporation, Inc., Sapporo, Hokkaido, Japan, for their assistance in the animal experiments.

Funding

This work was partially supported by JSPS KAKENHI Grant Number JP18K0703708.

Author information

Authors and Affiliations

  1. Section of Biological Science, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Hokkaido, 066-0052, Japan

    Teppei Nakamura & Osamu Tatsumi

  2. Laboratory of Anatomy, Division of Veterinary Medicine, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Hokkaido, 060-0818, Japan

    Teppei Nakamura, Osamu Ichii, Masataka Chihara, Yaser Hosny Ali Elewa & Yasuhiro Kon

  3. Medical Zoology Group, Department of Infectious Diseases, Hokkaido Institute of Public Health, Sapporo, Hokkaido, 060-0819, Japan

    Takao Irie & Hirokazu Kouguchi

  4. Sankyo Labo Service Corporation, Inc., Sapporo, Hokkaido, 004-0802, Japan

    Kozue Sotozaki

  5. Laboratory of Veterinary Pathology, Faculty of Agriculture, Tottori University, Tottori, 680-0945, Japan

    Yuji Sunden

  6. Section of Biological Safety Research, Tama Laboratory, Japan Food Research Laboratories, Tama, Tokyo, 206-0025, Japan

    Ken-ichi Nagasaki

  7. Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt

    Yaser Hosny Ali Elewa

Authors
  1. Teppei Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Osamu Ichii
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takao Irie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hirokazu Kouguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kozue Sotozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masataka Chihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuji Sunden
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ken-ichi Nagasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Osamu Tatsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yaser Hosny Ali Elewa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasuhiro Kon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhiro Kon.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of Hokkaido Institute of Public Health (approval No. K27-03). This article does not contain any studies with human participants performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamura, T., Ichii, O., Irie, T. et al. Cotton rat (Sigmodon hispidus) develops metabolic disorders associated with visceral adipose inflammation and fatty pancreas without obesity. Cell Tissue Res 375, 483–492 (2019). https://doi.org/10.1007/s00441-018-2908-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-018-2908-9

Keywords

Search

Navigation