From mice to men – mouse models in obesity research: What can we learn?

summary

Obesity has become a world-wide epidemic and is associated with diseases such as diabetes, dyslipidaemia, cardiovascular disease and certain types of cancers. Understanding the adipose tissue developmental process, involving adipogenesis, angiogenesis and extracellular matrix remodelling, is therefore crucial to reveal the pathobiology of obesity. Experimental mouse models are extensively used to gain new insights into these processes and to evaluate the role of new key players, in particular proteolytic system components, in adipose tissue development and obesity. In this paper, we will review available in vitro and in vivo murine models of obesity and discuss their value in understanding the mechanisms contributing to obesity.

Keywords

Animal models - obesity - transgenic animals

• References

• 1 Sethi JK. Activatin' human adipose progenitors in obesity. Diabetes 2010; 59: 2354-2357.
• 2 Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev 2004; 84: 277-359.
• 3 Mokdad AH, Ford ES, Bowman BA. et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. J Am Med Assoc 2003; 289: 76-79.
• 4 Bray GA, Bellanger T. Epidaemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine 2006; 29: 109-117.
• 5 Ahima RS. Adipose tissue as an endocrine organ. Obesity 2006; 14 (Suppl. 05) 242S-9S.
• 6 Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature 2006; 444: 875-880.
• 7 Cummings DE, Schwartz MW. Genetics and pathophysiology of human obesity. Annu Rev Med 2003; 54: 453-471.
• 8 Bost F, Caron L, Marchetti I. et al. Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage. Biochem J 2002; 361: 621-627.
• 9 Dani C. Embryonic stem cell-derived adipogenesis. Cells Tissues Organs 1999; 165: 173-180.
• 10 Vogel CF, Matsumura F. Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induced adipocyte differentiation in mouse embryonic fibroblasts (MEFs) involves tyrosine kinase c-Src. Biochem Pharmacol 2003; 66: 1231-1244.
• 11 Green H, Kehinde O. Spontaneous heritable changes leading to increased adipose conversion in 3T3 cells. Cell 1976; 7: 105-113.
• 12 Green H, Kehinde O. Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol 1979; 101: 169-171.
• 13 Chang TH, Polakis SE. Differentiation of 3T3-L1 fibroblasts to adipocytes. Effect of insulin and indomethacin on the levels of insulin receptors. J Biol Chem 1978; 253: 4693-4696.
• 14 Costa M, Manen CA, Russell DH. In vivo activation of cAMP-dependent protein kinase by aminophylline and 1-methyl, 3-isobutylxanthine. Biochem Biophys Res Commun 1975; 65: 75-81.
• 15 Elks ML, Manganiello VC, Vaughan M. Hormone-sensitive particulate cAMP phosphodiesterase activity in 3T3-L1 adipocytes. Regulation of responsiveness by dexamethasone. J Biol Chem 1983; 258: 8582-8587.
• 16 Student AK, Hsu RY, Lane MD. Induction of fatty acid synthetase synthesis in differentiating 3T3-L1 preadipocytes. J Biol Chem 1980; 255: 4745-4750.
• 17 Ramirez-Zacarias JL, Castro-Munozledo F, Kuri-Harcuch W. Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil red O. Histochemistry 1992; 97: 493-497.
• 18 Hom FG, Goodner CJ, Berrie MA. A [3H]2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo. Validation of the model and the absence of an insulin effect on brain. Diabetes 1984; 33: 141-152.
• 19 Vidal N, Cavaille JP, Poggi M. et al. A nonradioisotope chemiluminescent assay for evaluation of 2-deoxyglucose uptake in 3T3-L1 adipocytes. Effect of various carbonyls species on insulin action. Biochimie 2012; 94: 2569-2576.
• 20 Yea K, Kim J, Lim S. et al. Lysophosphatidylserine regulates blood glucose by enhancing glucose transport in myotubes and adipocytes. Biochem Biophys Res Commun 2009; 378: 783-788.
• 21 Green H, Meuth M. An established pre-adipose cell line and its differentiation in culture. Cell 1974; 3: 127-133.
• 22 Mandrup S, Loftus TM, MacDougald OA. et al. Obese gene expression at in vivo levels by fat pads derived from s.c. implanted 3T3-F442A preadipocytes. Proc Natl Acad Sci USA 1997; 94: 4300-4305.
• 23 West DB, York B. Dietary fat, genetic predisposition, and obesity: lessons from animal models. Am J Clin Nutr 1998; 67: 505S-512S.
• 24 Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011; 2011: 197636.
• 25 Singer JB, Hill AE, Burrage LC. et al. Genetic dissection of complex traits with chromosome substitution strains of mice. Science 2004; 304: 445-448.
• 26 Burrage LC, Baskin-Hill AE, Sinasac DS. et al. Genetic resistance to diet-induced obesity in chromosome substitution strains of mice. Mamm Genome 2010; 21: 115-129.
• 27 Warden CH, Fisler JS. Comparisons of diets used in animal models of high-fat feeding. Cell Metab 2008; 7: 277.
• 28 Backhed F, Ding H, Wang T. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101: 15718-15723.
• 29 Ranadive SA, Vaisse C. Lessons from extreme human obesity: monogenic disorders. Endocrinol Metab Clin North Am 2008; 37: 733-751. x
• 30 Kanasaki K, Koya D. Biology of obesity: lessons from animal models of obesity. J Biomed Biotechnol 2011; 2011: 197636.
• 31 Gonet AE, Renold AE. Increase in number and size of the islands of Langerhans with obesity and diabetes in the spiny mouse (Acomys). Schweiz Med Wochenschr 1966; 96: 735-736.
• 32 Sandholt CH, Hansen T, Pedersen O. Beyond the fourth wave of genome-wide obesity association studies. Nutr Diabetes 2012; 2: e37.
• 33 Bultman SJ, Michaud EJ, Woychik RP. Molecular characterisation of the mouse agouti locus. Cell 1992; 71: 1195-1204.
• 34 Lu D, Willard D, Patel IR. et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994; 371: 799-802.
• 35 Brannian JD, Furman GM, Diggins M. Declining fertility in the lethal yellow mouse is related to progressive hyperleptinemia and leptin resistance. Reprod Nutr Dev 2005; 45: 143-150.
• 36 Klebig ML, Wilkinson JE, Geisler JG. et al. Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc Natl Acad Sci USA 1995; 92: 4728-4732.
• 37 Mynatt RL, Miltenberger RJ, Klebig ML. et al. Combined effects of insulin treatment and adipose tissue-specific agouti expression on the development of obesity. Proc Natl Acad Sci USA 1997; 94: 919-922.
• 38 Hotamisligil GS, Johnson RS, Distel RJ. et al. Uncoupling of obesity from insulin resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science 1996; 274: 1377-1379.
• 39 Wilson BD, Ollmann MM, Kang L. et al. Structure and function of ASP, the human homolog of the mouse agouti gene. Hum Mol Genet 1995; 4: 223-230.
• 40 Zhang Y, Proenca R, Maffei M. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425-432.
• 41 Chen H, Charlat O, Tartaglia LA. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996; 84: 491-495.
• 42 Hasty AH, Shimano H, Osuga J. et al. Severe hypercholesterolemia, hypertriglyceridemia, and atherosclerosis in mice lacking both leptin and the low density lipoprotein receptor. J Biol Chem 2001; 276: 37402-37408.
• 43 Kusminski CM, Holland WL, Sun K. et al. MitoNEET-driven alterations in adipocyte mitochondrial activity reveal a crucial adaptive process that preserves insulin sensitivity in obesity. Nat Med 2012; 18: 1539-1549.
• 44 Kluge R, Scherneck S, Schurmann A. et al. Pathophysiology and genetics of obesity and diabetes in the New Zealand obese mouse: a model of the human metabolic syndrome. Methods Mol Biol 2012; 933: 59-73.
• 45 Suzuki W, Iizuka S, Tabuchi M. et al. A new mouse model of spontaneous diabetes derived from ddY strain. Exp Anim 1999; 48: 181-189.
• 46 Iizuka S, Suzuki W, Tabuchi M. et al. Diabetic complications in a new animal model (TSOD mouse) of spontaneous NIDDM with obesity. Exp Anim 2005; 54: 71-83.
• 47 Miyata S, Yamada N, Kawada T. Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in tsumura suzuki obese diabetes mice. Biol Pharm Bull 2012; 35: 1784-1793.
• 48 Hirayama I, Yi Z, Izumi S. et al. Genetic analysis of obese diabetes in the TSOD mouse. Diabetes 1999; 48: 1183-1191.
• 49 Allan MF, Eisen EJ, Pomp D. The M16 mouse: an outbred animal model of early onset polygenic obesity and diabesity. Obes Res 2004; 12: 1397-1407.
• 50 Srinivasan K, Ramarao P. Animal models in type 2 diabetes research: an overview. Indian J Med Res 2007; 125: 451-472.
• 51 Reddi AS, Camerini-Davalos RA. Hereditary diabetes in the KK mouse: an overview. Adv Exp Med Biol 1988; 246: 7-15.
• 52 Kobayashi M, Kawashima H, Takemori K. et al. Ternatin, a cyclic peptide isolated from mushroom, and its derivative suppress hyperglycemia and hepatic fatty acid synthesis in spontaneously diabetic KK-A(y) mice. Biochem Biophys Res Commun 2012; 427: 299-304.
• 53 Takada M, Sumi M, Maeda A. et al. Pyrroloquinoline quinone, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signalling in C2C12 myotubes and improves impaired glucose tolerance in diabetic KK-A(y) mice. Biochem Biophys Res Commun 2012; 428: 315-320.
• 54 Neels JG, Thinnes T, Loskutoff DJ. Angiogenesis in an in vivo model of adipose tissue development. FASEB J 2004; 18: 983-985.
• 55 Cao Y. Adipose tissue angiogenesis as a therapeutic target for obesity and metabolic diseases. Nature reviews Drug discovery 2010; 9: 107-115.
• 56 Lijnen HR. Angiogenesis and obesity. Cardiovasc Res 2008; 78: 286-293.
• 57 Hlatky L, Hahnfeldt P, Folkman J. Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. J Natl Cancer Inst 2002; 94: 883-893.
• 58 Cao R, Brakenhielm E, Wahlestedt C. et al. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci USA 2001; 98: 6390-6395.
• 59 Lijnen HR. Role of fibrinolysis in obesity and thrombosis. Thromb Res 2009; 123 (Suppl. 04) S46-S49.
• 60 Lijnen HR, Collen D. Mechanisms of physiological fibrinolysis. Baillieres Clin Haematol 1995; 8: 277-290.
• 61 Shaw DA, Machaughton D. Relationship between blood fibrinoytic activity and body fatness. Lancet 1963; 1: 352-354.
• 62 De Taeye BM, Novitskaya T, Gleaves L. et al. Bone marrow plasminogen activator inhibitor-1 influences the development of obesity. J Biol Chem 2006; 281: 32796-32805.
• 63 Hoover-Plow J, Ellis J, Yuen L. In vivo plasminogen deficiency reduces fat accumulation. Thromb Haemost 2002; 87: 1011-1019.
• 64 Lijnen HR. Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice. Thromb Haemost 2005; 93: 816-819.
• 65 Lijnen HR. Deficiency of alpha2-antiplasmin does not affect murine adipose tissue development. J Thromb Haemost 2007; 5: 420-421.
• 66 Lijnen HR, Frederix L, Scroyen I. Deficiency of plasminogen activator inhibitor-2 impairs nutritionally induced murine adipose tissue development. J Thromb Haemost 2007; 5: 2259-2265.
• 67 Lijnen HR, Maquoi E, Morange P. et al. Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscl Thromb Vasc Biol 2003; 23: 78-84.
• 68 Ma LJ, Mao SL, Taylor KL. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53: 336-346.
• 69 Morange PE, Bastelica D, Bonzi MF. et al. Influence of t-pA and u-PA on adipose tissue development in a murine model of diet-induced obesity. Thromb Haemost 2002; 87: 306-310.
• 70 Morange PE, Lijnen HR, Alessi MC. et al. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscl Thromb Vasc Biol 2000; 20: 1150-1154.
• 71 Schafer K, Fujisawa K, Konstantinides S. et al. Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 2001; 15: 1840-1842.
• 72 Scroyen I, Christiaens V, Lijnen HR. No functional role of plasminogen activator inhibitor-1 in murine adipogenesis or adipocyte differentiation. J Thromb Haemost 2007; 5: 139-145.
• 73 Scroyen I, Jacobs F, Cosemans L. et al. Effect of plasminogen activator inhibitor-1 on adipogenesis in vivo. Thromb Haemost 2009; 101: 388-393.
• 74 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Ann Rev Cell Develop Biol 2001; 17: 463-516.
• 75 Gomez DE, Alonso DF, Yoshiji H. et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997; 74: 111-122.
• 76 Demeulemeester D, Scroyen I, Voros G. et al. Overexpression of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in mice does not affect adipogenesis or adipose tissue development. Thromb Haemost 2006; 95: 1019-1024.
• 77 Jaworski DM, Sideleva O, Stradecki HM. et al. Sexually dimorphic diet-induced insulin resistance in obese tissue inhibitor of metalloproteinase-2 (TIMP-2)-deficient mice. Endocrinology 2011; 152: 1300-1313.
• 78 Lijnen HR, Demeulemeester D, Van Hoef B. et al. Deficiency of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) impairs nutritionally induced obesity in mice. Thromb Haemost 2003; 89: 249-255.
• 79 Lijnen HR, Van HB, Frederix L. et al. Adipocyte hypertrophy in stromelysin-3 deficient mice with nutritionally induced obesity. Thromb Haemost 2002; 87: 530-535.
• 80 Lijnen HR, Van Hoef B, Rodriguez JA. et al. Stromelysin-2 (MMP-10) deficiency does not affect adipose tissue formation in a mouse model of nutritionally induced obesity. Biochem Biophys Res Commun 2009; 389: 378-381.
• 81 Maquoi E, Demeulemeester D, Voros G. et al. Enhanced nutritionally induced adipose tissue development in mice with stromelysin-1 gene inactivation. Thromb Haemost 2003; 89: 696-704.
• 82 Pendas AM, Folgueras AR, Llano E. et al. Diet-induced obesity and reduced skin cancer susceptibility in matrix metalloproteinase 19-deficient mice. Mol Cell Biol 2004; 24: 5304-5313.
• 83 Scroyen I, Cosemans L, Lijnen HR. Effect of tissue inhibitor of matrix metalloproteinases-1 on in vitro and in vivo adipocyte differentiation. Thromb Res 2009; 124: 578-583.
• 84 Scroyen I, Jacobs F, Cosemans L. et al. Blood vessel density in de novo formed adipose tissue is decreased upon overexpression of TIMP-1. Obesity 2010; 18: 638-640.
• 85 Stradecki HM, Jaworski DM. Hyperphagia and leptin resistance in tissue inhibitor of metalloproteinase-2 deficient mice. J Neuroendocrinol 2011; 23: 269-281.
• 86 Van Hul M, Lijnen HR. A functional role of gelatinase A in the development of nutritionally induced obesity in mice. J Thromb Haemost 2008; 6: 1198-1206.
• 87 Van Hul M, Lijnen HR. Effect of weight loss on gelatinase levels in obese mice. Clin Exp Pharmacol Physiol 2011; 38: 647-649.
• 88 Van Hul M, Piccard H, Lijnen HR. Gelatinase B (MMP-9) deficiency does not affect murine adipose tissue development. Thromb Haemost 2010; 104: 165-171.