Animal models of obesity and diabetes mellitus

Key Points

  • Development of safe and potent therapeutics is required to combat the obesity and diabetes mellitus pandemic

  • Animal models remain indispensable for discovering, validating and optimizing novel therapeutics for their safe use in humans

  • To improve the transition from bench to bedside, researchers must select the appropriate models, beware a myriad of confounding factors and draw appropriate conclusions

  • Experimental procedures and conditions should be accurately detailed to improve the reproducibility and translation of findings in preclinical animal models

  • Different animal models, ranging from non-mammalian models to non-human primates, each have distinct advantages and limitations

Abstract

More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

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Figure 1: Key advantages and disadvantages of different classes of animal models used in obesity and diabetes research.
Figure 2: Important experimental parameters and potential confounders of experimental outcomes in obesity and diabetes research and their interrelatedness.

References

  1. 1

    Finkelstein, E. A. et al. Obesity and severe obesity forecasts through 2030. Am. J. Preventive Med. 42, 563–570 (2012).

  2. 2

    Malik, V. S., Willett, W. C. & Hu, F. B. Global obesity: trends, risk factors and policy implications. Nat. Rev. Endocrinol. 9, 13–27 (2013).

  3. 3

    Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

  4. 4

    El-Sayed Moustafa, J. S. & Froguel, P. From obesity genetics to the future of personalized obesity therapy. Nat. Rev. Endocrinol. 9, 402–413 (2013).

  5. 5

    Banting, F. G., Best, C. H., Collip, J. B., Campbell, W. R. & Fletcher, A. A. Pancreatic extracts in the treatment of diabetes mellitus. Can. Med. Assoc. J. 12, 141–146 (1922).

  6. 6

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

  7. 7

    Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

  8. 8

    Hill, J. O., Wyatt, H. R. & Peters, J. C. Energy balance and obesity. Circulation 126, 126–132 (2012).

  9. 9

    Klil-Drori, A. J., Azoulay, L. & Pollak, M. N. Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing? Nat. Rev. Clin. Oncol. 14, 85–99 (2017).

  10. 10

    Redline, S. et al. Risk factors for sleep-disordered breathing in children. Am. J. Respir. Crit. Care Med. 159, 1527–1532 (1999).

  11. 11

    Becerra, M. B., Becerra, B. J. & Teodorescu, M. Healthcare burden of obstructive sleep apnea and obesity among asthma hospitalizations: results from the U. S.-based Nationwide Inpatient Sample. Respiratory Med. 117, 230–236 (2016).

  12. 12

    Figueroa-Munoz, J., Chinn, S. & Rona, R. Association between obesity and asthma in 4–11 year old children in the UK. Thorax 56, 133–137 (2001).

  13. 13

    Muc, M., Mota-Pinto, A. & Padez, C. Association between obesity and asthma — epidemiology, pathophysiology and clinical profile. Nutr. Res. Rev. 29, 194–201 (2016).

  14. 14

    Stenius-Aarniala, B. et al. Immediate and long term effects of weight reduction in obese people with asthma: randomised controlled study. BMJ 320, 827–832 (2000).

  15. 15

    Stampfer, M. J., Maclure, K. M., Colditz, G. A., Manson, J. E. & Willett, W. C. Risk of symptomatic gallstones in women with severe obesity. Am. J. Clin. Nutr. 55, 652–658 (1992).

  16. 16

    Tilg, H. & Hotamisligil, G. S. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology 131, 934–945 (2006).

  17. 17

    D'Agati, V. D. et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat. Rev. Nephrol. 12, 453–471 (2016).

  18. 18

    Ebbeling, C. B., Pawlak, D. B. & Ludwig, D. S. Childhood obesity: public-health crisis, common sense cure. Lancet 360, 473–482 (2002).

  19. 19

    Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

  20. 20

    Bournat, J. C. & Brown, C. W. Mitochondrial dysfunction in obesity. Curr. Opin. Endocrinol. Diabetes Obes. 17, 446–452 (2010).

  21. 21

    Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

  22. 22

    Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).

  23. 23

    Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

  24. 24

    Feldstein, A. E. et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. Hepatology 40, 185–194 (2004).

  25. 25

    Unger, R. H. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol. Metab. 14, 398–403 (2003).

  26. 26

    Fasshauer, M. & Blüher, M. Adipokines in health and disease. Trends Pharmacol Sci. 36, 461–470 (2015).

  27. 27

    Hotamisligil, G. S. & Bernlohr, D. A. Metabolic functions of FABPs[mdash]mechanisms and therapeutic implications. Nat. Rev. Endocrinol. 11, 592–605 (2015).

  28. 28

    Fosbol, M. O. & Zerahn, B. Contemporary methods of body composition measurement. Clin. Physiol. Funct. Imag. 35, 81–97 (2015).

  29. 29

    Brommage, R. Validation and calibration of DEXA body composition in mice. Am. J. Physiol. Endocrinol. Metab. 285, E454–E459 (2003).

  30. 30

    Nixon, J. P. et al. Evaluation of a quantitative magnetic resonance imaging system for whole body composition analysis in rodents. Obesity 18, 1652–1659 (2010).

  31. 31

    James, J. R. et al. Fat and water 1H MRI to investigate effects of leptin in obese mice. Obesity 17, 2089–2093 (2009).

  32. 32

    Torgerson, J. S., Hauptman, J., Boldrin, M. N. & Sjostrom, L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 27, 155–161 (2003).

  33. 33

    Van Gaal, L. F., Rissanen, A. M., Scheen, A. J., Ziegler, O. & Rossner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 365, 1389–1397 (2005).

  34. 34

    Pi-Sunyer, X. et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015).

  35. 35

    Smith, S. R. et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363, 245–256 (2010).

  36. 36

    Tschöp, M. H. et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell. Metab. 24, 51–62 (2016).

  37. 37

    Henderson, S. J. et al. Robust anti-obesity and metabolic effects of a dual GLP-1/glucagon receptor peptide agonist in rodents and non-human primates. Diabetes Obes. Metab. 18, 1176–1190 (2016).

  38. 38

    Finan, B. et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36 (2015).

  39. 39

    Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749–757 (2009).

  40. 40

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02692781 (2016).

  41. 41

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02119819 (2015).

  42. 42

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02205528 (2017).

  43. 43

    Watts, J. L. Fat synthesis and adiposity regulation in Caenorhabditis elegans. Trends Endocrinol. Metab. 20, 58–65 (2009).

  44. 44

    Trinh, I. & Boulianne, G. L. Modeling obesity and its associated disorders in Drosophila. Physiology 28, 117–124 (2013).

  45. 45

    Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003).

  46. 46

    Pospisilik, J. A. et al. Drosophila genome-wide obesity screen reveals Hedgehog as a determinant of brown versus white adipose cell fate. Cell 140, 148–160 (2010).

  47. 47

    Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell. Metab. 6, 280–293 (2007).

  48. 48

    Leopold, P. & Perrimon, N. Drosophila and the genetics of the internal milieu. Nature 450, 186–188 (2007).

  49. 49

    Oka, T. et al. Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity. BMC Physiol. 10, 21–34 (2010).

  50. 50

    Mair, W., Piper, M. D. W. & Partridge, L. Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol. 3, 1305–1311 (2005).

  51. 51

    Skorupa, D. A., Dervisefendic, A., Zwiener, J. & Pletcher, S. D. Dietary composition specifies consumption, obesity and lifespan in Drosophila melanogaster. Aging Cell 7, 478–490 (2008).

  52. 52

    Gumienny, T. L. & Savage-Dunn, C. in WormBook (ed The C. elegans Research Community) https://doi.org/10.1895/wormbook.1.22.2 (2005).

  53. 53

    Mansfeld, J. et al. Branched-chain amino acid catabolism is a conserved regulator of physiological ageing. Nat. Commun. 6, 10043 (2015).

  54. 54

    Yan, J. et al. Obesity- and aging-induced excess of central transforming growth factor-beta potentiates diabetic development via an RNA stress response. Nat. Med. 20, 1001–1008 (2014).

  55. 55

    Al-Anzi, B. et al. Obesity-blocking neurons in Drosophila. Neuron 63, 329–341 (2009).

  56. 56

    Cruz, S. A., Tseng, Y. C., Kaiya, H. & Hwang, P. P. Ghrelin affects carbohydrate-glycogen metabolism via insulin inhibition and glucagon stimulation in the zebrafish (Danio rerio) brain. Comp Biochem Physiol A Mol Integr Physiol. 156, 190–200 (2010).

  57. 57

    Gorissen, M., Bernier, N. J., Nabuurs, S. B., Flik, G. & Huising, M. O. Two divergent leptin paralogues in zebrafish (Danio rerio) that originate early in teleostean evolution. J. Endocrinol. 201, 329–339 (2009).

  58. 58

    Song, Y. & Cone, R. D. Creation of a genetic model of obesity in a teleost. FASEB J. 21, 2042–2049 (2007).

  59. 59

    Bharucha, K. N., Tarr, P. & Zipursky, S. L. A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis. J. Exp. Biol. 211, 3103–3110 (2008).

  60. 60

    Polakof, S., Panserat, S., Soengas, J. L. & Moon, T. W. Glucose metabolism in fish: a review. J. Comp. Physiol. B 182, 1015–1045 (2012).

  61. 61

    Pierce, S. B. et al. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 15, 672–686 (2001).

  62. 62

    Brogiolo, W. et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr. Biol. 11, 213–221 (2001).

  63. 63

    Papasani, M. R., Robison, B. D., Hardy, R. W. & Hill, R. A. Early developmental expression of two insulins in zebrafish (Danio rerio). Physiol. Genom. 27, 79–85 (2006).

  64. 64

    Luong, N. et al. Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell. Metab. 4, 133–142 (2006).

  65. 65

    Morris, S. N. S. et al. Development of diet-induced insulin resistance in adult Drosophila melanogaster. Biochim. Biophys. Acta 1822, 1230–1237 (2012).

  66. 66

    Olsen, A. S., Sarras, M. P. & Intine, R. V. Limb regeneration is impaired in an adult zebrafish model of diabetes mellitus. Wound Repair Regen 18, 532–542 (2010).

  67. 67

    Wang, Y., Rovira, M., Yusuff, S. & Parsons, M. J. Genetic inducible fate mapping in larval zebrafish reveals origins of adult insulin-producing β-cells. Development 138, 609–617 (2011).

  68. 68

    Parsons, M. J. et al. Notch-responsive cells initiate the secondary transition in larval zebrafish pancreas. Mech. Dev. 126, 898–912 (2009).

  69. 69

    Moro, E., Gnügge, L., Braghetta, P., Bortolussi, M. & Argenton, F. Analysis of beta cell proliferation dynamics in zebrafish. Dev. Biol. 332, 299–308 (2009).

  70. 70

    Lin, J. W. et al. Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas. Dev. Biol. 270, 474–486 (2004).

  71. 71

    Rovira, M. et al. Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation. Proc. Natl Acad. Sci. USA 108, 19264–19269 (2011).

  72. 72

    Hill, J. H., Franzosa, E. A., Huttenhower, C. & Guillemin, K. A conserved bacterial protein induces pancreatic beta cell expansion during zebrafish development. eLife 5, e20145 (2016).

  73. 73

    Rulifson, E. J., Kim, S. K. & Nusse, R. Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296, 1118–1120 (2002).

  74. 74

    Schlotterer, A. et al. C. elegans as model for the study of high glucose-mediated life span reduction. Diabetes 58, 2450–2456 (2009).

  75. 75

    Birse, R. T. et al. High fat diet-induced obesity and heart dysfunction is regulated by the TOR pathway in Drosophila. Cell Metab. 12, 533–544 (2010).

  76. 76

    Capiotti, K. M. et al. Hyperglycemia induces memory impairment linked to increased acetylcholinesterase activity in zebrafish (Danio rerio). Behav. Brain Res. 274, 319–325 (2014).

  77. 77

    Rees, D. A. & Alcolado, J. C. Animal models of diabetes mellitus. Diabet. Med. 22, 359–370 (2005).

  78. 78

    Bray, G. A. & York, D. A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol. Rev. 59, 719–809 (1979).

  79. 79

    Herberg, L. & Coleman, D. L. Laboratory animals exhibiting obesity and diabetes syndromes. Metabolism 26, 59–99 (1977).

  80. 80

    Pickup, J. C. in Textbook of Diabetes (eds Pickup, J. C. & Williams, G.) 23.1–23.25 (Blackwell Science, 1997).

  81. 81

    European Commission. Seventh Report on the Statistics on the Number of Animals used for Experimental and other Scientific Purposes in the Member States of the European Union (European Commission, 2013).

  82. 82

    Nilsson, C., Raun, K., Yan, F. f., Larsen, M. O. & Tang-Christensen, M. Laboratory animals as surrogate models of human obesity. Acta Pharmacol. Sin. 33, 173–181 (2012).

  83. 83

    Surwit, R. S., Kuhn, C. M., Cochrane, C., McCubbin, J. A. & Feinglos, M. N. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37, 1163–1167 (1988).

  84. 84

    Winzell, M. S. & Ahren, B. The high-fat diet-fed mouse. Diabetes 53, S215–S219 (2004).

  85. 85

    Leibowitz, S. F. et al. Phenotypic profile of SWR/J and A/J mice compared to control strains: possible mechanisms underlying resistance to obesity on a high-fat diet. Brain Res. 1047, 137–147 (2005).

  86. 86

    Surwit, R. S. et al. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and AJ mice. Metabolism 44, 645–651 (1995).

  87. 87

    West, D. B., Boozer, C. N., Moody, D. L. & Atkinson, R. L. Dietary obesity in nine inbred mouse strains. Am. J. Physiol. Regul. Integr. Comp. Physiol. 262, R1025–R1032 (1992).

  88. 88

    Parks, B. W. et al. Genetic architecture of insulin resistance in the mouse. Cell Metab. 21, 334–346 (2015).

  89. 89

    Attie, A. D. & Keller, M. P. in Gene Co-Expression Modules and Type 2 Diabetes (eds Meyerhof, W., Beisiegel, U. & Joost, H. G.) 47–56 (Springer, 2010).

  90. 90

    Leiter, E. H. Mice with targeted gene disruptions or gene insertions for diabetes research: problems, pitfalls, and potential solutions. Diabetologia 45, 296–308 (2002).

  91. 91

    Mekada, K. et al. Genetic differences among C57BL/6 substrains. Exp. Animals 58, 141–149 (2009).

  92. 92

    Kahle, M. et al. Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis. Mol. Metab. 2, 435–446 (2013).

  93. 93

    Schemmel, R., Mickelsen, O. & Gill, J. L. Dietary obesity in rats: body weight and body fat accretion in seven strains of rats. J. Nutr. 100, 1041–1048 (1970).

  94. 94

    Levin, B. E., Dunn-Meynell, A. A., Balkan, B. & Keesey, R. E. Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 273, R725–R730 (1997).

  95. 95

    The International Mouse Knockout Consortium. A mouse for all reasons. Cell 128, 9–13 (2007).

  96. 96

    Karp, N. A. et al. Prevalence of sexual dimorphism in mammalian phenotypic traits. Nat. Commun. 8, 15475 (2017).

  97. 97

    International Mouse Phenotyping Consortium. http://www.mousephenotype.org/ (2017).

  98. 98

    Pi, J. et al. Persistent oxidative stress due to absence of uncoupling protein 2 associated with impaired pancreatic β-cell function. Endocrinology 150, 3040–3048 (2009).

  99. 99

    Wolfer, D. P., Crusio, W. E. & Lipp, H. P. Knockout mice: simple solutions to the problems of genetic background and flanking genes. Trends Neurosci. 25, 336–340 (2002).

  100. 100

    Attane, C. et al. Differential insulin secretion of high-fat diet-fed C57BL/6NN and C57BL/6NJ mice: implications of mixed genetic background in metabolic studies. PLoS ONE 11, e0159165 (2016).

  101. 101

    Fontaine, D. A. & Davis, D. B. Attention to background strain is essential for metabolic research: C57BL/6 and the International Knockout Mouse Consortium. Diabetes 65, 25–33 (2016).

  102. 102

    Hong, J., Stubbins, R. E., Smith, R. R., Harvey, A. E. & Nunez, N. P. Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr. J. 8, 11–16 (2009).

  103. 103

    Stubbins, R. E., Holcomb, V. B., Hong, J. & Nunez, N. P. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur. J. Nutr. 51, 861–870 (2012).

  104. 104

    Yang, Y., Smith, D. L., Keating, K. D., Allison, D. B. & Nagy, T. R. Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice. Obesity 22, 2147–2155 (2014).

  105. 105

    Nadal-Casellas, A., Proenza, A. M., Llado, I. & Gianotti, M. Sex-dependent differences in rat hepatic lipid accumulation and insulin sensitivity in response to diet-induced obesity. Biochem. Cell Biol. 90, 164–172 (2012).

  106. 106

    Garg, N., Thakur, S., Alex McMahan, C. & Adamo, M. L. High fat diet induced insulin resistance and glucose intolerance are gender-specific in IGF-1R heterozygous mice. Biochem. Biophys. Res. Commun. 413, 476–480 (2011).

  107. 107

    Hevener, A., Reichart, D., Janez, A. & Olefsky, J. Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes 51, 1907–1912 (2002).

  108. 108

    Medrikova, D. et al. Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control. Int. J. Obes. 36, 262–272 (2012).

  109. 109

    Pettersson, U. S., Walden, T. B., Carlsson, P. O., Jansson, L. & Phillipson, M. Female mice are protected against high-fat diet induced metabolic syndrome and increase the regulatory T cell population in adipose tissue. PLoS ONE 7, e46057 (2012).

  110. 110

    Geer, E. B. & Shen, W. Gender differences in insulin resistance, body composition, and energy balance. Gend Med. 6, 60–75 (2009).

  111. 111

    Hoeg, L. D. et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes 60, 64–73 (2010).

  112. 112

    Logue, J. et al. Do men develop type 2 diabetes at lower body mass indices than women? Diabetologia 54, 3003–3006 (2011).

  113. 113

    ter Horst, K. W. et al. Sexual dimorphism in hepatic, adipose tissue, and peripheral tissue insulin sensitivity in obese humans. Front. Endocrinol. 6, 182–188 (2015).

  114. 114

    Kautzky-Willer, A., Harreiter, J. & Pacini, G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus. Endocr. Rev. 37, 278–316 (2016).

  115. 115

    NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in, N. R. F. 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387, 1377–1396 (2016).

  116. 116

    Lee, M. J., Wu, Y. & Fried, S. K. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol. Aspects Med. 34, 1–11 (2013).

  117. 117

    Clegg, D. J., Riedy, C. A., Smith, K. A. B., Benoit, S. C. & Woods, S. C. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52, 682–687 (2003).

  118. 118

    Macotela, Y., Boucher, J., Tran, T. T. & Kahn, C. R. Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 58, 803–812 (2009).

  119. 119

    Jeffery, E. et al. The adipose tissue microenvironment regulates depot-specific adipogenesis in obesity. Cell. Metab. 24, 142–150 (2016).

  120. 120

    Clegg, D. J., Brown, L. M., Woods, S. C. & Benoit, S. C. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55, 978–987 (2006).

  121. 121

    Chen, X. et al. The number of X chromosomes causes sex differences in adiposity in mice. PLoS Genet. 8, e1002709 (2012).

  122. 122

    Link, J. C. et al. Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression. BMC Genomics 18, 89–100 (2017).

  123. 123

    Link, J. C., Chen, X., Arnold, A. P. & Reue, K. Metabolic impact of sex chromosomes. Adipocyte 2, 74–79 (2013).

  124. 124

    Mauvais-Jarvis, F., Arnold, A. P. & Reue, K. A. Guide for the design of pre-clinical studies on sex differences in metabolism. Cell. Metab. 25, 1216–1230 (2017).

  125. 125

    Wang, S. et al. Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet. 2, e15 (2006).

  126. 126

    McCullough, L. D. et al. NIH initiative to balance sex of animals in preclinical studies: generative questions to guide policy, implementation, and metrics. Biol. Sex. Differ. 5, 15–22 (2014).

  127. 127

    Klein, S. L. et al. Opinion: Sex inclusion in basic research drives discovery. Proc. Natl Acad. Sci. USA 112, 5257–5258 (2015).

  128. 128

    Becker, J. B., Prendergast, B. J. & Liang, J. W. Female rats are not more variable than male rats: a meta-analysis of neuroscience studies. Biol. Sex. Differ. 7, 34–41 (2016).

  129. 129

    Villareal, D. T., Apovian, C. M., Kushner, R. F. & Klein, S. Obesity in older adults: technical review and position statement of the American Society for Nutrition and NAASO, The Obesity Society. Am. J. Clin. Nutr. 82, 923–934 (2005).

  130. 130

    Cree, M. G. et al. Intramuscular and liver triglycerides are increased in the elderly. J. Clin. Endocrinol. Metab. 89, 3864–3871 (2004).

  131. 131

    Shimokata, H. et al. Age as independent determinant of glucose tolerance. Diabetes 40, 44–51 (1991).

  132. 132

    Jackson, R. A. Mechanisms of age-related glucose intolerance. Diabetes Care 13, 9 (1990).

  133. 133

    van der Heijden, R. A. et al. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis. Sci. Rep. 5, 16474–16489 (2015).

  134. 134

    Houtkooper, R. H. et al. The metabolic footprint of aging in mice. Sci. Rep. 1, 134–145 (2011).

  135. 135

    Nadiv, O., Cohen, O. & Zick, Y. Defects of insulin's signal transduction in old rat livers. Endocrinology 130, 1515–1524 (1992).

  136. 136

    Elahi, D., Muller, D. C., Andersen, D. K., Tobin, J. D. & Andres, R. The effect of age and glucose concentration on insulin secretion by the isolated perfused rat pancreas. Endocrinology 116, 11–16 (1985).

  137. 137

    Perfetti, R., Rafizadeh, C. M., Liotta, A. S. & Egan, J. M. Age-dependent reduction in insulin secretion and insulin mRNA in isolated islets from rats. Am. J. Physiol. Endocrinol. Metab. 269, E983 (1995).

  138. 138

    Leiter, E. H., Premdas, F., Harrison, D. E. & Lipson, L. G. Aging and glucose homeostasis in C57BL/6J male mice. FASEB J. 2, 2807–2811 (1988).

  139. 139

    Klimas, J. E. Oral glucose tolerance during the life-span of a colony of rats. J. Gerontol. 23, 31–34 (1968).

  140. 140

    Lamming, D. W. et al. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell 12, 712–718 (2013).

  141. 141

    Nishikawa, S., Yasoshima, A., Doi, K., Nakayama, H. & Uetsuka, K. Involvement of sex, strain and age factors in high fat diet-induced obesity in C57BL/6J and BALB/cA mice. Exp. Animals 56, 263–272 (2007).

  142. 142

    Kubant, R. et al. A comparison of effects of lard and hydrogenated vegetable shortening on the development of high-fat diet-induced obesity in rats. Nutr. Diabetes 5, e188 (2015).

  143. 143

    Timmers, S. et al. Differential effects of saturated versus unsaturated dietary fatty acids on weight gain and myocellular lipid profiles in mice. Nutr. Diabetes 1, e11 (2011).

  144. 144

    Lucas, F., Ackroff, K. & Sclafani, A. Dietary fat-induced hyperphagia in rats as a function of fat type and physical form. Physiol. Behav. 45, 937–946 (1989).

  145. 145

    Sclafani, A. Carbohydrate-induced hyperphagia and obesity in the rat: effects of saccharide type, form, and taste. Neurosci. Biobehav. Rev. 11, 155–162 (1987).

  146. 146

    Kübeck, R. et al. Dietary fat and gut microbiota interactions determine diet-induced obesity in mice. Mol. Metab. 5, 1162–1174 (2016).

  147. 147

    Fleissner, C. K. et al. Absence of intestinal microbiota does not protect mice from diet-induced obesity. Br. J. Nutr. 104, 919–929 (2010).

  148. 148

    Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).

  149. 149

    Desmarchelier, C. et al. Diet-induced obesity in ad libitum-fed mice: food texture overrides the effect of macronutrient composition. Br. J. Nutr. 109, 1518–1527 (2013).

  150. 150

    Warden, C. H. & Fisler, J. S. Comparisons of diets used in animal models of high fat feeding. Cell Metab. 7, 277–280 (2008).

  151. 151

    Chassaing, B. et al. Lack of soluble fiber drives diet-induced adiposity in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G528–G541 (2015).

  152. 152

    Lephart, E. D., Setchell, K. D. R., Handa, R. J. & Lund, T. D. Behavioral effects of endocrine-disrupting substances: phytoestrogens. ILAR J. 45, 443–454 (2004).

  153. 153

    Vadiveloo, M., Scott, M., Quatromoni, P., Jacques, P. & Parekh, N. Trends in dietary fat intake and high-fat foods from 1991–2008 in the Framingham Heart Study participants. Br. J. Nutr. 111, 724–734 (2014).

  154. 154

    Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

  155. 155

    Kless, C. et al. Diet-induced obesity causes metabolic impairment independent of alterations in gut barrier integrity. Mol. Nutr. Food Res. 59, 968–978 (2015).

  156. 156

    Müller, V. M. et al. Gut barrier impairment by high-fat diet in mice depends on housing conditions. Mol. Nutr. Food Res. 60, 897–908 (2016).

  157. 157

    Bray, G. A., Nielsen, S. J. & Popkin, B. M. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am. J. Clin. Nutr. 79, 537–543 (2004).

  158. 158

    Powell, E. S., Smith-Taillie, L. P. & Popkin, B. M. Added sugars intake across the distribution of US children and adult consumers: 1977–2012. J. Acad. Nutr. Dietet. 116, 1543–1550 (2016).

  159. 159

    Stanhope, K. L. et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J. Clin. Invest. 119, 1322–1334 (2009).

  160. 160

    Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J. M. & Lustig, R. H. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat. Rev. Gastroenterol. Hepatol. 7, 251–264 (2010).

  161. 161

    Jurgens, H. et al. Consuming fructose-sweetened beverages increases body adiposity in mice. Obes. Res. 13, 1146–1156 (2005).

  162. 162

    Sumiyoshi, M., Sakanaka, M. & Kimura, Y. Chronic intake of high-fat and high-sucrose diets differentially affects glucose intolerance in mice. J. Nutr. 136, 582–587 (2006).

  163. 163

    Lozano, I. et al. High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr. Metab. 13, 15 (2016).

  164. 164

    Avena, N. M., Rada, P. & Hoebel, B. G. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci. Biobehav. Rev. 32, 20–39 (2008).

  165. 165

    la Fleur, S. E., Luijendijk, M. C. M., van der Zwaal, E. M., Brans, M. A. D. & Adan, R. A. H. The snacking rat as model of human obesity: effects of a free-choice high-fat high-sugar diet on meal patterns. Int. J. Obes. 38, 643–649 (2014).

  166. 166

    Kless, C., Rink, N., Rozman, J. & Klingenspor, M. Proximate causes for diet-induced obesity in laboratory mice: a case study. Eur. J. Clin. Nutr. 71, 306–317 (2017).

  167. 167

    Sampey, B. P. et al. Cafeteria diet is a robust model of human metabolic syndrome with liver and adipose inflammation: comparison to high-fat diet. Obesity 19, 1109–1117 (2011).

  168. 168

    Johnson, P. M. & Kenny, P. J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat. Neurosci. 13, 635–641 (2010).

  169. 169

    Berg, C. et al. Eating patterns and portion size associated with obesity in a Swedish population. Appetite 52, 21–26 (2009).

  170. 170

    Beckers, J., Wurst, W. & de Angelis, M. H. Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling. Nat. Rev. Genet. 10, 371–380 (2009).

  171. 171

    Patten, B. C. Network Orientors: Steps Toward a Cosmography of Ecosystems: Orientors for Directional Development, Self-Organization, and Autoevolution in Eco Targets, Goal Functions, and Orientors (eds Müller, F. & Leupelt, M.) 137–160 (Springer, 1998).

  172. 172

    Schaefer, S. & Nadeau, J. H. The genetics of epigenetic inheritance: modes, molecules, and mechanisms. Q. Rev. Biol. 90, 381–415 (2015).

  173. 173

    Sasson, I. E., Vitins, A. P., Mainigi, M. A., Moley, K. H. & Simmons, R. A. Pre-gestational versus gestational exposure to maternal obesity differentially programs the offspring in mice. Diabetologia 58, 615–624 (2015).

  174. 174

    Borengasser, S. J. et al. Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. Endocrinology 154, 4113–4125 (2013).

  175. 175

    Shankar, K. et al. Maternal overweight programs insulin and adiponectin signaling in the offspring. Endocrinology 151, 2577–2589 (2010).

  176. 176

    Shankar, K. et al. Maternal obesity at conception programs obesity in the offspring. Am. J. Physiol. Regul. Integr. Comp. Physiol. 294, R528–R538 (2008).

  177. 177

    Wei, Y. et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc. Natl Acad. Sci. USA 111, 1873–1878 (2014).

  178. 178

    Ng, S. F. et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467, 963–966 (2010).

  179. 179

    Fullston, T. et al. Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content. FASEB J. 27, 4226–4243 (2013).

  180. 180

    Huypens, P. et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat. Genet. 48, 497–499 (2016).

  181. 181

    Kivimaki, M. et al. Substantial intergenerational increases in body mass index are not explained by the fetal overnutrition hypothesis: the Cardiovascular Risk in Young Finns Study. Am. J. Clin. Nutr. 86, 1509–1514 (2007).

  182. 182

    Fox, C. S. et al. Trends in the association of parental history of obesity over 60 years. Obesity 22, 919–924 (2014).

  183. 183

    Lake, J. K., Power, C. & Cole, T. J. Child to adult body mass index in the 1958 British birth cohort: associations with parental obesity. Arch. Dis. Child. 77, 376–380 (1997).

  184. 184

    Meigs, J. B., Cupples, L. A. & Wilson, P. W. Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes 49, 2201–2207 (2000).

  185. 185

    Grandjean, V. et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci. Rep. 5, 18193–18202 (2015).

  186. 186

    Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).

  187. 187

    Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).

  188. 188

    Vickers, M. & Sloboda, D. Strategies for reversing the effects of metabolic disorders induced as a consequence of developmental programming. Front. Physiol. 3, 242–253 (2012).

  189. 189

    Masuyama, H., Mitsui, T., Nobumoto, E. & Hiramatsu, Y. The effects of high-fat diet exposure in utero on the obesogenic and diabetogenic traits through epigenetic changes in adiponectin and leptin gene expression for multiple generations in female mice. Endocrinology 156, 2482–2491 (2015).

  190. 190

    Hervey, G. R. The effects of lesions in the hypothalamus in parabiotic rats. J. Physiol. 145, 336–352 (1959).

  191. 191

    Coleman, D. L. & Hummel, K. P. Effects of parabiosis of normal with genetically diabetic mice. Am. J. Physiol. 217, 1298–1304 (1969).

  192. 192

    Coleman, D. L. Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298 (1973).

  193. 193

    Morton, G. J., Meek, T. H. & Schwartz, M. W. Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15, 367–378 (2014).

  194. 194

    Farooqi, I. S. & O'Rahilly, S. Genetics of obesity in humans. Endocr. Rev. 27, 710–718 (2006).

  195. 195

    Coleman, D. L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14, 141–148 (1978).

  196. 196

    Trayhurn, P. & Thurlby, P. L., & James, W. P. T. Thermogenic defect in pre-obese ob/ob mice. Nature 266, 60–62 (1977).

  197. 197

    Himms-Hagen, J. & Desautels, M. A mitochondrial defect in brown adipose tissue of the obese (obob) mouse: reduced binding of purine nucleotides and a failure to respond to cold by an increase in binding. Biochem. Biophys. Res. Commun. 83, 628–634 (1978).

  198. 198

    Thurlby, P. L. & Trayhurn, P. Regional blood flow in genetically obese (ob/ob) mice. Pflügers Arch. 385, 193–201 (1980).

  199. 199

    Swerdloff, R. S., Batt, R. A. & Bray, G. A. Reproductive hormonal function in the genetically obese (ob/ob) mouse. Endocrinology 98, 1359–1364 (1976).

  200. 200

    Dubuc, P. U. Basal corticosterone levels of young ob/ob mice. Horm. Metab. Res. 9, 95–97 (1977).

  201. 201

    Gat-Yablonski, G. & Phillip, M. Leptin and regulation of linear growth. Curr. Opin. Clin. Nutr. Metab. Care 11, 303–308 (2008).

  202. 202

    Coleman, D. L. & Hummel, K. P. The influence of genetic background on the expression of the obese (ob) gene in the mouse. Diabetologia 9, 287–293 (1973).

  203. 203

    Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

  204. 204

    Farooqi, I. S. et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J. Clin. Invest. 110, 1093–1103 (2002).

  205. 205

    Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).

  206. 206

    Phillips, M. S. et al. Leptin receptor missense mutation in the fatty Zucker rat. Nat. Genet. 13, 18–19 (1996).

  207. 207

    Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

  208. 208

    Wu-Peng, X. S. et al. Phenotype of the obese Koletsky (f) rat due to Tyr763Stop mutation in the extracellular domain of the leptin receptor (Lepr): evidence for deficient plasma-to-CSF transport of leptin in both the Zucker and Koletsky obese rat. Diabetes 46, 513–518 (1997).

  209. 209

    Chua, S. C. et al. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr). Diabetes 45, 1141–1143 (1996).

  210. 210

    Friedman, J. E. et al. Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Am. J. Physiol. Endocrinol. Metab. 273, E1014–E1023 (1997).

  211. 211

    Koletsky, S. Obese spontaneously hypertensive rats — a model for study of atherosclerosis. Exp. Mol. Pathol. 19, 53–60 (1973).

  212. 212

    Peterson, R. G., Shaw, W. N., Neel, M. A., Little, L. A. & Eichberg, J. Zucker diabetic fatty rat as a model for non-insulin-dependent diabetes mellitus. ILAR J. 32, 16–19 (1990).

  213. 213

    Kawano, K. et al. Spontaneous long-term hyperglycemic rat with diabetic complications: Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes 41, 1422–1428 (1992).

  214. 214

    Moran, T. H. Unraveling the obesity of OLETF rats. Physiol. Behav. 94, 71–78 (2008).

  215. 215

    Dockray, G. J. Cholecystokinin and gut-brain signalling. Regul. Pept. 155, 6–10 (2009).

  216. 216

    Bi, S., Scott, K. A., Hyun, J., Ladenheim, E. E. & Moran, T. H. Running wheel activity prevents hyperphagia and obesity in Otsuka Long-Evans Tokushima Fatty rats: role of hypothalamic signaling. Endocrinology 146, 1676–1685 (2005).

  217. 217

    Clemmensen, C. et al. Gut-brain cross-talk in metabolic control. Cell 168, 758–774 (2017).

  218. 218

    Day, C. & Bailey, C. J. Effect of the antiobesity agent sibutramine in obese-diabetic ob/ob mice. Int. J. Obes. 22, 619–623 (1998).

  219. 219

    Liu, J., Lee, J., Hernandez, M. A. S., Mazitschek, R. & Ozcan, U. Treatment of obesity with celastrol. Cell 161, 999–1011 (2015).

  220. 220

    Scrocchi, L. A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996).

  221. 221

    Hansotia, T. et al. Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J. Clin. Invest. 117, 143–152 (2007).

  222. 222

    Finan, B., Clemmensen, C. & Müller, T. D. Emerging opportunities for the treatment of metabolic diseases: glucagon-like peptide-1 based multi-agonists. Mol. Cell. Endocrinol. 418, 42–54 (2015).

  223. 223

    Edwards, A. M. et al. Too many roads not taken. Nature 470, 163–165 (2011).

  224. 224

    de Angelis, M. H. et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nat. Genet. 47, 969–978 (2015).

  225. 225

    Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  226. 226

    Schwartz, M. W. & Porte, D. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

  227. 227

    Baumeier, C. et al. Hepatic DPP4 DNA methylation associates with fatty liver. Diabetes 66, 25–35 (2017).

  228. 228

    Kammel, A. et al. Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. Hum. Mol. Genet. 25, 2588–2599 (2016).

  229. 229

    Levin, B. E., Triscari, J., Hogan, S. & Sullivan, A. C. Resistance to diet-induced obesity: food intake, pancreatic sympathetic tone, and insulin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 252, R471–R478 (1987).

  230. 230

    Clegg, D. J. et al. Reduced anorexic effects of insulin in obesity-prone rats fed a moderate-fat diet. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R981–R986 (2005).

  231. 231

    Levin, B. E. & Dunn-Meynell, A. A. Reduced central leptin sensitivity in rats with diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, R941–R948 (2002).

  232. 232

    Levin, B. E., Dunn-Meynell, A. A. & Banks, W. A. Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R143–R150 (2003).

  233. 233

    Kaiser, N. et al. Psammomys obesus, a model for environment-gene interactions in type 2 diabetes. Diabetes 54, S137–S144 (2005).

  234. 234

    Walder, K. R., Fahey, R. P., Morton, G. J., Zimmet, P. Z. & Collier, G. R. Characterization of obesity phenotypes in Psammomys obesus (Israeli sand rats). Int. J. Exp. Diabetes Res. 1, 177–184 (2000).

  235. 235

    Scherzer, P. et al. Psammomys obesus, a particularly important animal model for the study of the human diabetic nephropathy. Anat. Cell Biol. 44, 176–185 (2011).

  236. 236

    Spolding, B. et al. Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli sand rat). PLoS ONE 9, e92656 (2014).

  237. 237

    Leiter, E. H. & Reifsnyder, P. C. Differential levels of diabetogenic stress in two new mouse models of obesity and type 2 diabetes. Diabetes 53, S4–S11 (2004).

  238. 238

    Kluge, R., Scherneck, S., Schürmann, A. & Joost, H. G. in Animal Models in Diabetes Research (Joost, H. G., Al-Hasani, H. & Schürmann, A.) 59–73 (Humana Press, 2012).

  239. 239

    Veroni, M. C., Proietto, J. & Larkins, R. G. Evolution of insulin resistance in New Zealand obese mice. Diabetes 40, 1480–1487 (1991).

  240. 240

    Mirhashemi, F. et al. Diet dependence of diabetes in the New Zealand Obese (NZO) mouse: total fat, but not fat quality or sucrose accelerates and aggravates diabetes. Exp. Clin. Endocrinol. Diabetes 119, 167–171 (2011).

  241. 241

    Jurgens, H. S. et al. Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction. Diabetologia 50, 1481–1489 (2007).

  242. 242

    Kluth, O. et al. Dissociation of lipotoxicity and glucotoxicity in a mouse model of obesity associated diabetes: role of forkhead box O1 (FOXO1) in glucose-induced beta cell failure. Diabetologia 54, 605–616 (2011).

  243. 243

    Schwenk, R. W. et al. GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. Diabetologia 58, 604–614 (2015).

  244. 244

    Lubura, M. et al. Diabetes prevalence in NZO females depends on estrogen action on liver fat content. Am. J. Physiol. Endocrinol. Metab. 309, E968–E980 (2015).

  245. 245

    Baumeier, C. et al. Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. Biochim. Biophys. Acta 1851, 566–576 (2015).

  246. 246

    Kim, J. H. & Saxton, A. M. in Animal Models in Diabetes Research (Joost, H. G., Al-Hasani, H. & Schürmann, A.) 75–87 (Humana Press, 2012).

  247. 247

    Kim, J. H. et al. Phenotypic characterization of polygenic type 2 diabetes in TALLYHO/JngJ mice. J. Endocrinol. 191, 437–446 (2006).

  248. 248

    Wang, Y., Nishina, P. M. & Naggert, J. K. Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng. J. Endocrinol. 203, 65–74 (2009).

  249. 249

    Devlin, M. J. et al. Early-Onset Type 2 Diabetes Impairs Skeletal Acquisition in the Male TALLYHO/JngJ Mouse. Endocrinology 155, 3806–3816 (2014).

  250. 250

    Cummings, B. P. et al. Development and characterization of a novel rat model of type 2 diabetes mellitus: the UC Davis type 2 diabetes mellitus UCD-T2DM rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1782–R1793 (2008).

  251. 251

    Fields, A. J. et al. Alterations in intervertebral disc composition, matrix homeostasis and biomechanical behavior in the UCD-T2DM rat model of type 2 diabetes. J. Orthop. Res. 33, 738–746 (2015).

  252. 252

    Agrawal, R. et al. Deterioration of plasticity and metabolic homeostasis in the brain of the UCD-T2DM rat model of naturally occurring type-2 diabetes. Biochim. Biophys. Acta 1842, 1313–1323 (2014).

  253. 253

    Cummings, B. P. et al. Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. Proc. Natl Acad. Sci. USA 108, 14670–14675 (2011).

  254. 254

    Cummings, B. P. et al. Chronic administration of the glucagon-like peptide-1 analog, liraglutide, delays the onset of diabetes and lowers triglycerides in UCD-T2DM rats. Diabetes 59, 2653–2661 (2010).

  255. 255

    Cummings, B. P. et al. Administration of pioglitazone alone or with alogliptin delays diabetes onset in UCD-T2DM rats. J. Endocrinol. 221, 133–144 (2014).

  256. 256

    Cummings, B. P. et al. Ileal interposition surgery improves glucose and lipid metabolism and delays diabetes onset in the UCD-T2DM rat. Gastroenterology 138, 2437–2446 (2010).

  257. 257

    Cummings, B. P. et al. Vertical sleeve gastrectomy improves glucose and lipid metabolism and delays diabetes onset in UCD-T2DM rats. Endocrinology 153, 3620–3632 (2012).

  258. 258

    Halban, P. A. et al. β-Cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. J. Clin. Endocrinol. Metab. 99, 1983–1992 (2014).

  259. 259

    Talchai, C., Xuan, S., Lin, H. V., Sussel, L. & Accili, D. Pancreatic β-cell dedifferentiation as mechanism of diabetic β-cell failure. Cell 150, 1223–1234 (2012).

  260. 260

    Fuchsberger, C. et al. The genetic architecture of type 2 diabetes. Nature 536, 41–47 (2016).

  261. 261

    Goto, Y., Kakizaki, M. & Masaki, N. Production of spontaneous diabetic rats by repetition of selective breeding. Tohoku J. Exp. Med. 119, 85–90 (1976).

  262. 262

    Movassat, J., Saulnier, C. & Portha, B. Beta-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus. Diabete Metab. 21, 365–370 (1995).

  263. 263

    Portha, B. Programmed disorders of β-cell development and function as one cause for type 2 diabetes? The GK rat paradigm. Diabetes Metab. Res. Rev. 21, 495–504 (2005).

  264. 264

    Oyadomari, S. et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J. Clin. Invest. 109, 525–532 (2002).

  265. 265

    Wang, J. et al. A mutation in the insulin 2 gene induces diabetes with severe pancreatic β-cell dysfunction in the Mody mouse. J. Clin. Invest. 103, 27–37 (1999).

  266. 266

    Yoshioka, M., Kayo, T., Ikeda, T. & Koizuni, A. A. Novel locus, Mody4, Distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) nutant mice. Diabetes 46, 887–894 (1997).

  267. 267

    Hattersley, A. T. & Pearson, E. R. Minireview: Pharmacogenetics and beyond: the interaction of therapeutic response, β-cell physiology, and genetics in diabetes. Endocrinology 147, 2657–2663 (2006).

  268. 268

    Wang, Z., York, N. W., Nichols, C. G. & Remedi, M. S. Pancreatic β-cell dedifferentiation in diabetes and re-differentiation following insulin therapy. Cell Metab. 19, 872–882 (2014).

  269. 269

    Brereton, M. F. et al. Reversible changes in pancreatic islet structure and function produced by elevated blood glucose. Nat. Commun. 5, 4639–4650 (2014).

  270. 270

    Koster, J. C., Marshall, B. A., Ensor, N., Corbett, J. A. & Nichols, C. G. Targeted overactivity of β cell KATP channels induces profound neonatal diabetes. Cell 100, 645–654 (2000).

  271. 271

    Remedi, M. S. et al. Secondary consequences of β-cell inexcitability: identification and prevention in a murine model of KATP-induced neonatal diabetes mellitus. Cell Metab. 9, 140–151 (2009).

  272. 272

    Dukes, I. D. et al. Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1α-deficient mice. J. Biol. Chem. 273, 24457–24464 (1998).

  273. 273

    Toye, A. A. et al. A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. Diabetes 53, 1577–1583 (2004).

  274. 274

    Froguel, P. et al. Familial hyperglycemia due to mutations in glucokinase — definition of a subtype of diabetes mellitus. N. Engl. J. Med. 328, 697–702 (1993).

  275. 275

    Vionnet, N. et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356, 721–722 (1992).

  276. 276

    McDonald, T. J. & Ellard, S. Maturity onset diabetes of the young: identification and diagnosis. Ann. Clin. Biochem. 50, 403–415 (2013).

  277. 277

    Ahlgren, U., Jonsson, J., Jonsson, L., Simu, K. & Edlund, H. β-Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes. Genes Dev. 12, 1763–1768 (1998).

  278. 278

    Brissova, M. et al. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J. Biol. Chem. 277, 11225–11232 (2002).

  279. 279

    Bastidas-Ponce, A. et al. Foxa2 and Pdx1 cooperatively regulate postnatal maturation of pancreatic β-cells. Mol. Metab. 6, 524–534 (2017).

  280. 280

    King, B. M. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol. Behav. 87, 221–244 (2006).

  281. 281

    Mitchel, J. S. & Keesey, R. E. Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: evidence from a restriction-refeeding regimen. Physiol. Behav. 18, 1121–1125 (1977).

  282. 282

    Bonner-Weir, S., Trent, D. F. & Weir, G. C. Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release. J. Clin. Invest. 71, 1544–1553 (1983).

  283. 283

    Skovso, S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J. Diabetes Investig. 5, 349–358 (2014).

  284. 284

    Gilbert, E. R., Fu, Z. & Liu, D. Development of a nongenetic mouse model of type 2 diabetes. Exp. Diabetes Res. 2011, 416254 (2011).

  285. 285

    Reed, M. J. et al. A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49, 1390–1394 (2000).

  286. 286

    Levine, J. A. Measurement of energy expenditure. Public Health Nutr. 8, 1123–1132 (2005).

  287. 287

    Tschöp, M. H. et al. A guide to analysis of mouse energy metabolism. Nat. Methods 9, 57–63 (2011).

  288. 288

    Butler, A. A. & Kozak, L. P. A. Recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 59, 323 (2010).

  289. 289

    Speakman, J. R. Measuring energy metabolism in the mouse — theoretical, practical, and analytical considerations. Front. Physiol. 4, 34 (2013).

  290. 290

    Speakman, J. R., Fletcher, Q. & Vaanholt, L. The '39 steps': an algorithm for performing statistical analysis of data on energy intake and expenditure. Dis. Model. Mech. 6, 293–301 (2013).

  291. 291

    McMurray, F. et al. Adult onset global loss of the Fto gene alters body composition and metabolism in the mouse. PLoS Genet. 9, e1003166 (2013).

  292. 292

    Sorge, R. E. et al. Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nat. Methods 11, 629–632 (2014).

  293. 293

    Ussar, S. et al. Interactions between gut microbiota, host genetics and diet modulate the predisposition to obesity and metabolic syndrome. Cell Metab. 22, 516–530 (2015).

  294. 294

    Razzoli, M., Carboni, L., Andreoli, M., Ballottari, A. & Arban, R. Different susceptibility to social defeat stress of BalbC and C57BL6/J mice. Behav. Brain Res. 216, 100–108 (2011).

  295. 295

    Ergang, P. et al. Differential impact of stress on hypothalamic-pituitary-adrenal axis: gene expression changes in Lewis and Fisher rats. Psychoneuroendocrinology 53, 49–59 (2015).

  296. 296

    Krishnan, V. et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391–404 (2007).

  297. 297

    Martin, B., Ji, S., Maudsley, S. & Mattson, M. P. “Control” laboratory rodents are metabolically morbid: Why it matters. Proc. Natl Acad. Sci. USA 107, 6127–6133 (2010).

  298. 298

    Basterfield, L., Lumley, L. K. & Mathers, J. C. Wheel running in female C57BL/6J mice: impact of oestrus and dietary fat and effects on sleep and body mass. Int. J. Obes. 33, 212–218 (2009).

  299. 299

    Garrett, L., Lie, D. C., Hrabe de Angelis, M., Wurst, W. & Holter, S. M. Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests. BMC Neurosci. 13, 61 (2012).

  300. 300

    Sylow, L., Kleinert, M., Richter, E. A. & Jensen, T. E. Exercise-stimulated glucose uptake — regulation and implications for glycaemic control. Nat. Rev. Endocrinol. 13, 133–148 (2017).

  301. 301

    Bradley, R. L., Jeon, J. Y., Liu, F. F. & Maratos-Flier, E. Voluntary exercise improves insulin sensitivity and adipose tissue inflammation in diet-induced obese mice. Am. J. Physiol. Endocrinol. Metab. 295, E586–E594 (2008).

  302. 302

    Dumke, C. L. et al. Genetic selection of mice for high voluntary wheel running: effect on skeletal muscle glucose uptake. J. Appl. Physiol. 91, 1289–1297 (2001).

  303. 303

    Barres, R. & Zierath, J. R. The role of diet and exercise in the transgenerational epigenetic landscape of T2DM. Nat. Rev. Endocrinol. 12, 441–451 (2016).

  304. 304

    Cao, L. et al. Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142, 52–64 (2010).

  305. 305

    Cao, L. et al. White to brown fat phenotypic switch induced by genetic and environmental activation of a hypothalamic-adipocyte axis. Cell Metab. 14, 324–338 (2011).

  306. 306

    Beura, L. K. et al. Recapitulating adult human immune traits in laboratory mice by normalizing environment. Nature 532, 512–516 (2016).

  307. 307

    Rolfe, D. F. & Brown, G. C. Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol. Rev. 77, 731–758 (1997).

  308. 308

    Schwartz, M. W. et al. Evidence for entry of plasma insulin into cerebrospinal fluid through an intermediate compartment in dogs. Quantitative aspects and implications for transport. J. Clin. Invest. 88, 1272–1281 (1991).

  309. 309

    Chen, M., Woods, S. C. & Porte, D. Effect of cerebral intraventricular insulin on pancreatic insulin secretion in the dog. Diabetes 24, 910–914 (1975).

  310. 310

    Woods, S. C. & Porte, D. Effect of intracisternal insulin on plasma glucose and insulin in the dog. Diabetes 24, 905–909 (1975).

  311. 311

    Coate, K. C. et al. Portal vein glucose entry triggers a coordinated cellular response that potentiates hepatic glucose uptake and storage in normal but not high-fat/high-fructose-fed dogs. Diabetes 62, 392–400 (2013).

  312. 312

    Coate, K. C. et al. A high-fat, high-fructose diet accelerates nutrient absorption and impairs net hepatic glucose uptake in response to a mixed meal in partially pancreatectomized dogs. J. Nutr. 141, 1643–1651 (2011).

  313. 313

    Ionut, V. et al. Novel canine models of obese prediabetes and mild type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 298, E38–E48 (2010).

  314. 314

    Coate, K. C. et al. Chronic overeating impairs hepatic glucose uptake and disposition. Am. J. Physiol. Endocrinol. Metab. 308, E860–E867 (2015).

  315. 315

    Ellmerer, M. et al. Reduced access to insulin-sensitive tissues in dogs with obesity secondary to increased fat intake. Diabetes 55, 1769–1775 (2006).

  316. 316

    Kaiyala, K. J., Prigeon, R. L., Kahn, S. E., Woods, S. C. & Schwartz, M. W. Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs. Diabetes 49, 1525–1533 (2000).

  317. 317

    Coate, K. C. et al. Hepatic glucose uptake and disposition during short-term high-fat versus high-fructose feeding. Am. J. Physiol. Endocrinol. Metab. 307, E151–E160 (2014).

  318. 318

    Gifford, A. et al. Canine body composition quantification using 3 tesla fat-water MRI. J. Magn. Reson. Imag. 39, 485–491 (2014).

  319. 319

    Begg, D. P. et al. Insulin detemir is transported from blood to cerebrospinal fluid and has prolonged central anorectic action relative to NPH insulin. Diabetes 64, 2457–2466 (2015).

  320. 320

    Coate, K. C. et al. Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake. Am. J. Physiol. Endocrinol. Metab. 299, E887–E898 (2010).

  321. 321

    Verkest, K. R., Rand, J. S., Fleeman, L. M. & Morton, J. M. Spontaneously obese dogs exhibit greater postprandial glucose, triglyceride, and insulin concentrations than lean dogs. Domest. Animal Endocrinol. 42, 103–112 (2012).

  322. 322

    Verkest, K. R., Fleeman, L. M., Morton, J. M., Ishioka, K. & Rand, J. S. Compensation for obesity-induced insulin resistance in dogs: assessment of the effects of leptin, adiponectin, and glucagon-like peptide-1 using path analysis. Domest. Animal Endocrinol. 41, 24–34 (2011).

  323. 323

    Banfield Pet Hospital. Banfield Pet Hospital's state of pet health 2016 report https://www.banfield.com/Banfield/media/PDF/Downloads/soph/Banfield-State-of-Pet-Health-Report-2016.pdf (2016).

  324. 324

    Stevenson, R. W., Williams, P. E. & Cherrington, A. D. Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog. Diabetologia 30, 782–790 (1987).

  325. 325

    Keller, U., Cherrington, A. D. & Liljenquist, J. E. Ketone body turnover and net hepatic ketone production in fasted and diabetic dogs. Am. J. Physiol. Endocrinol. Metab. 235, E238–E248 (1978).

  326. 326

    Edgerton, D. S. & Cherrington, A. D. Glucagon as a critical factor in the pathology of diabetes. Diabetes 60, 377–380 (2011).

  327. 327

    Moore, M. C. et al. Diet-induced impaired glucose tolerance and gestational diabetes in the dog. J. Appl. Physiol. 110, 458–467 (2011).

  328. 328

    Coate, K. C. et al. Hepatic glucose metabolism in late pregnancy: normal versus high-fat and -fructose diet. Diabetes 62, 753–761 (2013).

  329. 329

    Hwang, J. H. et al. Impaired net hepatic glycogen synthesis in insulin-dependent diabetic subjects during mixed meal ingestion. A 13C nuclear magnetic resonance spectroscopy study. J. Clin. Invest. 95, 783–787 (1995).

  330. 330

    Davis, M. A., Williams, P. E. & Cherrington, A. D. Effect of a mixed meal on hepatic lactate and gluconeogenic precursor metabolism in dogs. Am. J. Physiol. Endocrinol. Metab. 247, E362–E369 (1984).

  331. 331

    Koopmans, S. J. & Schuurman, T. Considerations on pig models for appetite, metabolic syndrome and obese type 2 diabetes: from food intake to metabolic disease. Eur. J. Pharmacol. 759, 231–239 (2015).

  332. 332

    Renner, S. et al. Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research. Theriogenology 86, 406–421 (2016).

  333. 333

    Whitelaw, C. B., Sheets, T. P., Lillico, S. G. & Telugu, B. P. Engineering large animal models of human disease. J. Pathol. 238, 247–256 (2016).

  334. 334

    Renner, S. et al. Glucose intolerance and reduced proliferation of pancreatic β-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59, 1228–1238 (2010).

  335. 335

    Renner, S. et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 62, 1505–1511 (2013).

  336. 336

    Umeyama, K. et al. Dominant-negative mutant hepatocyte nuclear factor 1α induces diabetes in transgenic-cloned pigs. Transgen. Res. 18, 697–706 (2009).

  337. 337

    Shim, J., Al-Mashhadi, R. H., Sorensen, C. B. & Bentzon, J. F. Large animal models of atherosclerosis — new tools for persistent problems in cardiovascular medicine. J. Pathol. 238, 257–266 (2016).

  338. 338

    Klymiuk, N. et al. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes 61, 1527–1532 (2012).

  339. 339

    Klymiuk, N., Ludwig, B., Seissler, J., Reichart, B. & Wolf, E. Current concepts of using pigs as a source for beta-cell replacement therapy of type 1 diabetes. Curr. Mol. Biol. Rep. 2, 73–82 (2016).

  340. 340

    Kemter, E. et al. INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. Diabetologia 60, 1152–1156 (2017).

  341. 341

    Pound, L. D., Kievit, P. & Grove, K. L. The nonhuman primate as a model for type 2 diabetes. Curr. Opin. Endocrinol., Diabetes Obes. 21, 89–94 (2014).

  342. 342

    Scott, K. A. & Moran, T. H. The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R983–R987 (2007).

  343. 343

    Moran, T. H. et al. Peptide YY(3–36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R384–R388 (2005).

  344. 344

    Ahren, B., Baldwin, R. M. & Havel, P. J. Pharmacokinetics of human leptin in mice and rhesus monkeys. Int. J. Obes. 24, 1579–1585 (2000).

  345. 345

    Tang-Christensen, M., Havel, P. J., Jacobs, R. R., Larsen, P. J. & Cameron, J. L. Central administration of leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. J. Clin. Endocrinol. Metab. 84, 711–717 (1999).

  346. 346

    D'Alessio, D. A., Kieffer, T. J., Taborsky, J. & Havel, P. J. Activation of the parasympathetic nervous system is necessary for normal meal-induced insulin secretion in rhesus macaques. J. Clin. Endocrinol. Metab. 86, 1253–1259 (2001).

  347. 347

    Havel, P. J. & Valverde, C. Autonomic mediation of glucagon secretion during insulin-induced hypoglycemia in rhesus monkeys. Diabetes 45, 960–966 (1996).

  348. 348

    Cummings, B. P., Bremer, A. A., Kieffer, T. J., D'Alessio, D. & Havel, P. J. Investigation of the mechanisms contributing to the compensatory increase in insulin secretion during dexamethasone-induced insulin resistance in rhesus macaques. J. Endocrinol. 216, 207–215 (2013).

  349. 349

    Havel, P. J. & Ahren, B. Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin-induced hypoglycemia in women. Diabetes 46, 801–807 (1997).

  350. 350

    Ahren, B. & Holst, J. J. The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes 50, 1030–1038 (2001).

  351. 351

    Ramsey, J. J. et al. Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp. Gerontol. 35, 1131–1149 (2000).

  352. 352

    Mattison, J. A. et al. Impact of caloric restriction on health and survival in rhesus monkeys: the NIA study. Nature 489, 10–21 (2012).

  353. 353

    Kemnitz, J. W. Calorie restriction and aging in nonhuman primates. ILAR J. 52, 66–77 (2011).

  354. 354

    Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063–14075 (2017).

  355. 355

    Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

  356. 356

    Howard, C. F. Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 29, 301–306 (1986).

  357. 357

    Hansen, B. C. in Diabetes Mellitus: A Fundamental and Clinical Text (LeRoith, D., Taylor, S. I. & Olefsky, J. M.) 595–603 (Lippincott-Raven,1996).

  358. 358

    Hansen, B. C. Pathophysiology of obesity-associated type II diabetes (NIDDM): implications from longitudinal studies of non-human primates. Nutrition 5, 48–50 (1989).

  359. 359

    de Koning, E. J. P., Bodkin, N. L., Hansen, B. C. & Clark, A. Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36, 378–384 (1993).

  360. 360

    McCulloch, D. K., Kahn, S. E., Schwartz, M. W., Koerker, D. J. & Palmer, J. P. Effect of nicotinic acid-induced insulin resistance on pancreatic B cell function in normal and streptozocin-treated baboons. J. Clin. Invest. 87, 1395–1401 (1991).

  361. 361

    Higgins, P. B. et al. Eight week exposure to a high sugar high fat diet results in adiposity gain and alterations in metabolic biomarkers in baboons (Papio hamadryas sp.). Cardiovasc. Diabetol 9, 71–77 (2010).

  362. 362

    Wachtman, L. M. et al. Differential contribution of dietary fat and monosaccharide to metabolic syndrome in the common marmoset (Callithrix jacchus). Obesity 19, 1145–1156 (2011).

  363. 363

    Aagaard-Tillery, K. M. et al. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J. Mol. Endocrinol. 41, 91–102 (2008).

  364. 364

    Grant, W. F. et al. Perinatal exposure to a high-fat diet is associated with reduced hepatic sympathetic innervation in one-year old male Japanese macaques. PLoS ONE 7, e48119 (2012).

  365. 365

    Bremer, A. A. et al. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome, and type 2 diabetes. Clin. Transl Sci. 4, 243–252 (2011).

  366. 366

    Bremer, A. A. et al. Fish oil supplementation ameliorates fructose-induced hypertriglyceridemia and insulin resistance in adult male rhesus macaques. J. Nutr. 144, 5–11 (2014).

  367. 367

    Kavanagh, K. et al. Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Am. J. Clin. Nutr. 98, 349–357 (2013).

  368. 368

    Bose, T. et al. Identification of a QTL for adipocyte volume and of shared genetic effects between adipocyte volume with aspartate aminotransferase. Biochem. Genet. 48, 538–547 (2010).

  369. 369

    Kamath, S. et al. Coordinated defects in hepatic long chain fatty acid metabolism and triglyceride accumulation contribute to insulin resistance in non-human primates. PLoS ONE 6, e27617 (2011).

  370. 370

    Kramer, J. A. et al. The common marmoset as a model for the study of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Vet. Pathol. 52, 404–413 (2014).

  371. 371

    Swarbrick, M. M. et al. Inhibition of protein tyrosine phosphatase-1B with antisense oligonucleotides improves insulin sensitivity and increases adiponectin concentrations in monkeys. Endocrinology 150, 1670–1679 (2009).

  372. 372

    Adams, A. C. et al. LY2405319, an engineered FGF21 variant, improves the metabolic status of diabetic monkeys. PLoS ONE 8, e65763 (2013).

  373. 373

    Kharitonenkov, A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 148, 774–781 (2007).

  374. 374

    Nyborg, N. C., Molck, A. M., Madsen, L. W. & Bjerre Knudsen, L. The human GLP-1 analog liraglutide and the pancreas: evidence for the absence of structural pancreatic changes in three species. Diabetes 61, 1243–1249 (2012).

  375. 375

    Kievit, P. et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes 62, 490–497 (2013).

  376. 376

    Lin, J. C. et al. Appetite enhancement and weight gain by peripheral administration of TrkB agonists in non-human primates. PLoS ONE 3, e1900 (2008).

  377. 377

    Blevins, J. E. et al. Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308, R431–R438 (2015).

  378. 378

    Eberling, J. L., Roberts, J. A., Rapp, P. R., Tuszynski, M. H. & Jagust, W. J. Cerebral glucose metabolism and memory in aged rhesus macaques. Neurobiol. Aging 18, 437–443 (1997).

  379. 379

    Peters, A. et al. Neurobiological bases of age-related cognitive decline in the rhesus monkey. J. Neuropathol. Exp. Neurol. 55, 861–874 (1996).

  380. 380

    Moss, M. B. & Jonak, E. Cerebrovascular disease and dementia: A primate model of hypertension and cognition. Alzheimers Dementia 3, S6–S15 (2007).

  381. 381

    Bernier, M. et al. Resveratrol supplementation confers neuroprotection in cortical brain tissue of nonhuman primates fed a high-fat/sucrose diet. Aging 8, 899–914 (2016).

  382. 382

    Renner, S. et al. Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced β-cell mass. Diabetes 61, 2166–2175 (2012).

  383. 383

    Streckel, E. et al. Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition. J. Transl Med. 13, 73–86 (2015).

  384. 384

    Hinkel, R. et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J. Am. Coll. Cardiol. 69, 131–143 (2017).

  385. 385

    Kleinwort, K. J. H. et al. Retinopathy with central oedema in an INS C94Y transgenic pig model of long-term diabetes. Diabetologia 60, 1541–1549 (2017).

  386. 386

    Renner, S., Blutke, A., Streckel, E., Wanke, R. & Wolf, E. Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models. J. Pathol. 238, 345–358 (2016).

  387. 387

    Blutke, A. et al. The Munich MIDY Pig Biobank — a unique resource for studying organ crosstalk in diabetes. Mol. Metab. 6, 931–940 (2017).

  388. 388

    Hara, S., Umeyama, K., Yokoo, T., Nagashima, H. & Nagata, M. Diffuse glomerular nodular lesions in diabetic pigs carrying a dominant-negative mutant hepatocyte nuclear factor 1-alpha, an inheritant diabetic gene in humans. PLoS ONE 9, e92219 (2014).

  389. 389

    Al-Mashhadi, R. H. et al. Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant. Sci. Transl. Med. 5, 166ra1 (2013).

  390. 390

    Al-Mashhadi, R. H. et al. Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs. Diabetologia 58, 1926–1936 (2015).

  391. 391

    Wei, J. et al. Characterization of a hypertriglyceridemic transgenic miniature pig model expressing human apolipoprotein CIII. FEBS J. 279, 91–99 (2012).

  392. 392

    Shimatsu, Y. et al. Production of human apolipoprotein(a) transgenic NIBS miniature pigs by somatic cell nuclear transfer. Exp. Anim. 65, 37–43 (2016).

  393. 393

    Ozawa, M. et al. Production of cloned miniature pigs expressing high levels of human apolipoprotein(a) in plasma. PLoS ONE 10, e0132155 (2015).

  394. 394

    Li, Y. et al. Development of human-like advanced coronary plaques in low-density lipoprotein receptor knockout pigs and justification for statin treatment before formation of atherosclerotic plaques. J. Am. Heart Assoc. 5, e002779 (2016).

  395. 395

    Davis, B. T. et al. Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in yucatan miniature pigs. PLoS ONE 9, e93457 (2014).

  396. 396

    Amuzie, C. et al. A translational model for diet-related atherosclerosis: effect of statins on hypercholesterolemia and atherosclerosis in a minipig. Toxicol. Pathol. 44, 442–449 (2016).

  397. 397

    Tang, X. et al. Overexpression of porcine lipoprotein-associated phospholipase A2 in swine. Biochem. Biophys. Res. Commun. 465, 507–511 (2015).

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M.Kle. and M.H.T conceptualized the review. All authors wrote parts of the review article, contributed to discussion of content and reviewed and/or edited the manuscript before submission.

Correspondence to Matthias H. Tschöp.

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Amphid neuron

Sensory neurons found in the anterior head region of the nematode Caenorhabditis elegans.

Four core genotypes

A mouse model system that dissociates the effects of the gonadal sex (testes or ovaries) from the effects of the sex chromosomes (XX or XY)121.

Envirotype

Factors that are exogenous to an organism.

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Kleinert, M., Clemmensen, C., Hofmann, S. et al. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 14, 140–162 (2018). https://doi.org/10.1038/nrendo.2017.161

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