Obesity: Pathology and Therapy pp 461-489

Part of the Handbook of Experimental Pharmacology book series (HEP, volume 149)

Primates in the Experimental Pharmacology of Obesity

  • B. C. Hansen


Obesity in monkeys is a disease of maturity, with no reports to date of spontaneous juvenile onset obesity in any primate species. Monkeys are sexually mature at about the age of 4 years, and continue increasing in lean body mass and growth to about 7 years. From 7 years on some monkeys spontaneously and gradually develop excess body fatness, while others, maintained under identical conditions, remain lean all their lives. Interestingly, this adult-onset obesity develops while monkeys are being maintained on ad libitum feeding of a diet which is “ideal” in composition - low in fat, negligible in cholesterol, reasonable in protein, and high in fiber. The usual chow diet contains about 13% of calories as fat, 18% as protein, and 69% as digestible carbohydrates, with cholesterol content of about 83mg/kg diet. Composition of the diet is, therefore, not a significant factor in the development of spontaneous adult onset obesity in non-human primates. Obesity develops in free ranging monkeys (SCHWARTZ et al. 1993), of both sexes (SCHWARTZ et al. 1992), as well as in those maintained in a laboratory environment (JEN et al. 1985; KEMNITZ et al. 1986; HAMILTON et al. 1978).


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bodkin NL, Hansen BC (1995) Antihypertensive effects of captopril without adverse effects on glucose tolerance in hyperinsulinemic rhesus monkeys. J Med Primatol 24:1–6PubMedCrossRefGoogle Scholar
  2. Bodkin NL, Hansen BC, Young AA (1998) Dose-response for glucose lowering by Exendin-4 in diabetic rhesus monkeys (Macaca mulatta). Diabetes 47:A93CrossRefGoogle Scholar
  3. Bodki NL, Metzger BL, Hansen BC (1989) Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys. Am J Physiol 256:E676–E681Google Scholar
  4. Bodkin NL, Nicolson M, Ortmeyer HK, Hansen BC (1996) Hyperleptinemia: Relationship to adiposity and insulin resistance in the spontaneously obese rhesus monkey. Horm Metab Res 28:674–678PubMedCrossRefGoogle Scholar
  5. Bousquet-Melou A, Galitzky J, Carpene C, Lafontan M, Berlan M (1994) Adrenergic control of lipolysis in primate white fat cells: A comparative study with nonprimate mammals. Am J Physiol: Reg Int Comp Physiol 267:R115–R123Google Scholar
  6. Byrne M, Ulrich W, Katschinske M, Goke B (1998) GLP-1 improves first phase insulin secretion without altering insulin sensitivity in subjects with impaired glucose tolerance. Diabetes 47:A192CrossRefGoogle Scholar
  7. Christopher-Hennings J, Kurzman ID, Haffa, AL, Kemnitz JW, Mace wen EG (1995) The effect of high fat diet and dehydroepiandosterone (DHEA) administration in the rhesus monkey. In Vivo 9:415–420PubMedGoogle Scholar
  8. Coleman DL (1978) Obese and diabetes: Two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14:141–148PubMedCrossRefGoogle Scholar
  9. Cowan C et al. (1998) submittedGoogle Scholar
  10. DeOre K, Greig NH, Holloway HW, Wang Y, Perfetti R, Egan JM (1997) The effects of GLP-1 on insulin release in young and old rats in the fasting state and during an intravenous glucose tolerance test. J Gerontol 52 A:B245–B249Google Scholar
  11. Emorine LJ, Marullo S, Briend-Sutren M-M, Patey G, Tate K, Delavier-Klutchko C, Strosberg AD (1989) Molecular characterization of the human β3-adrenergic receptor. Science 245:1118–1121PubMedCrossRefGoogle Scholar
  12. Enocksson S, Shimizu M, Lonnqvist F, Nordenstrom J, Arner P (1995) Demonstration of an in vivo functional B-adrenoceptor in man. J Clin Invest 95:2239–2245PubMedCrossRefGoogle Scholar
  13. Fan Z, Kole H, Bernier M, Huang Z, Accilli D, Hansen BC, Shuldiner AR (1995) Molecular mechanism of insulin resistance in the spontaneously obese and diabetic rhesus monkey: site directed mutagenesis of the insulin receptor. The Endocrine Society 77:180Google Scholar
  14. Fehmann H-C, Goke R, Goke B (1992) Glucagon-like peptide-1 (7-37)(7-36) amide is a new incretin. Mol Cell Endocrinol 85:C39–C44PubMedCrossRefGoogle Scholar
  15. Fisher MH, Amend AM, Bach TJ, Barker JM, Brady EJ, Candelore MR, Carroll D, Casieri MA, Chiu S-HL, Deng L, Forrest MJ, Hegarty-Friscino B, Guan X-M, Horn GJ, Hutchins JE, Kelly LJ, Mathvink RJ, Metzger JM, Miller RR, Ok HO, Parmee ER, Saperstein R, Strader CD, Stearns RA, Thompson GM, Tota L, Vicaario PP, Weber AE, Woods JW, Wyvratt MJ, Zafian PT, Maclntyre DE (1998) A selective human beta 3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys. J Clin Invest (in press)Google Scholar
  16. Gong W, He Y, Karas M, Reitman M (1997) Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β3-adrenergic agonists, and leptin. J Biol Chem 272:24129–24132PubMedCrossRefGoogle Scholar
  17. Greenberg AS (1998) American Diabetes Association (oral communication)Google Scholar
  18. Grujic D, Susuli, VS, Harper M-E, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB (1997) β 3-adrenergic receptors on white and brown adipocytes mediate /23-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. J Biol Chem 272:17686–17693PubMedCrossRefGoogle Scholar
  19. Gutniak M, Orskov C, Hoist J. J, Ahren B, Efendic S (1992) Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus. New Engl J Med 326:1316–1322PubMedCrossRefGoogle Scholar
  20. Hamilton CL, Ciaccia P (1978) The course of development of glucose intolerance in the monkey (Macaca mulatto). J Med Primatol 7:165–173PubMedGoogle Scholar
  21. Hannah JS, Bodkin NL, Paidi MS, Anh-Le N, Howard BV, Hansen BC (1995) Effects of acipimox on the metabolism of free fatty acids and VLDL triglyceride. Acta Diabetologia 32:279–293CrossRefGoogle Scholar
  22. Hannah JS, Verdery RB, Bodkin NL, Hansen BC, Le N-A, Howard BV (1991) Changes in lipoprotein concentrations during the development of noninsulin dependent diabetes mellitus in obese rhesus monkeys (Macaca mulatto). J Clin Endocrinol Metab 72:1067–1072PubMedCrossRefGoogle Scholar
  23. Hansen BC, Bodkin NL (1985) Beta cell hyperresponsiveness to glucose precedes both fasting hyperinsulinemia and reduced glucose tolerance. (Abstract) Diabetes 34 [Suppl 1]:8AGoogle Scholar
  24. Hansen BC, Bodkin NL (1986) Heterogeneity of insulin responses: phases in the continuum leading to non-insulin-dependent diabetes mellitus. Diabetologia 29:713–719PubMedCrossRefGoogle Scholar
  25. Hansen BC, Bodkin NL (1990) β-cell hyperresponsiveness: earliest event in development of diabetes in monkeys. Am J Physiol 259 (Regulatory Integrative Comp Physiol 28):R612–R617PubMedGoogle Scholar
  26. Hansen, B. C, Jen, K.-L, Schwartz, J (1988) Changes in insulin responses and binding in adipocytes from monkeys with obesity progressing to diabetes. Int J Obes 12:391–401Google Scholar
  27. Hotta K, Gustafson TA, Ortmeyer HK, Bodkin NL, Hansen BC (1998) Monkey leptin receptor mRNA: Sequence, tissue distribution, and mRNA expression in the adipose tissue of normal, hyperinsulinemic and type 2 diabetic rhesus monkeys. Obes Res 6:353–360PubMedGoogle Scholar
  28. Hotta K, Gustafson TA, Ortmeyer HK, Bodkin NL, Nicolson,MA, Hansen BC (1996) Regulation of obese (ob) mRNA and plasma leptin levels in rhesus monkeys: Effects of insulin, body weight and diabetes. J Biol Chem 271:25327–25331PubMedCrossRefGoogle Scholar
  29. Hotta K, Gustafson TA, Yoshioka S, Ortmeyer HK, Bodkin NL, Hansen BC (1998) Relationships of PPARγand PPARγ2 mRNA levels to obesity, diabetes and hyperinsulinemia in rhesus monkeys. Int J Obesity 22:1000–1010CrossRefGoogle Scholar
  30. Huang Z, Hansen BC, Shuldiner AR (1993) Characterization of the insulin receptor gene in the rhesus monkey, a diabetes-prone species. Exp Clin Endocrinol 101:358–359Google Scholar
  31. Hudson JC, Baum ST, Frye DM, Roecker EB, Kemnitz JW (1996) Age and sex differences in body size and composition during rhesus monkey adulthood. Aging 8:197–204PubMedGoogle Scholar
  32. Jen K-LC, Hansen BC (1984) Feeding behavior during experimentally induced obesity in monkeys. Physiol Behav 33:863–869PubMedCrossRefGoogle Scholar
  33. Jen K-LC, Hansen BC, Metzger BL (1985) Adiposity, anthropometric measures, and plasma insulin levels of rhesus monkeys. Int J Obes 9:213–224PubMedGoogle Scholar
  34. Kates A-L, Park IRA, Himms-Hagen J, Mueller RW (1990) Thyroxine 5’-deiodinase in brown adipose tissue of the cynomolgus monkey Macaca fascicularis. Biochem Cell Biol 68:231–237PubMedCrossRefGoogle Scholar
  35. Kemnitz J, Francke, G (1986) Characteristics of spontaneous obesity in male rhesus monkeys. Physiol Behav 38:477–483PubMedCrossRefGoogle Scholar
  36. Kemnitz JW, Elson DF, Roecker EB, Baum ST, Bergman RN, Meglasson MD (1994) Pioglitazone increases insulin sensitivity, reduces blood glucose, insulin, and lipid levels, and lowers blood pressure, in obese, insulin-resistant rhesus monkeys. Diabetes 43:204–211PubMedCrossRefGoogle Scholar
  37. Kemnitz JW, Goy RW, Flitsch TJ, Lohmiller JJ, Robinson JA (1989) Obesity in male and female rhesus monkeys: fat distribution, glucoregulation, and serum androgen levels. J Clin Endocrinol Metab 69:287–293PubMedCrossRefGoogle Scholar
  38. Kennington AS, Hill CR, Craig J, Bogardus C, Raz I, Ortmeyer HK, Hansen BC, Romero G, Larner J (1990) Low urinary c/i/n?-inositol excretion in noninsulin-dependent diabetes mellitus. N Engl J Med 323:373–378PubMedCrossRefGoogle Scholar
  39. Larner J, Huang LC, Schwartz CFW, Oswald AS, Shen T-Y, Kinter M, Tang G, Zeller K (1988) Rat liver insulin mediator which stimulates pyruvate dehydrogenase phosphatase contains galactosamine and d-chiroinositol. Biochem Biophys Res Comm 151:1416–1426PubMedCrossRefGoogle Scholar
  40. Larner J, Huan, LC, Tang G, Suzuki S, Schwartz CFW, Romero G, Roulidis Z, Zeller K, Shen TY, Oswald AS, Luttrell L (1988) Insulin mediators: structure and function. Cold Spring Harb Symp Quant Biol 53:965–971PubMedGoogle Scholar
  41. Maclntyre DE (1998) Human β3 adrenergic receptor (/BAR) agonists: Acute and chronic effects in dogs and non human primates. Int J Obesity in pressGoogle Scholar
  42. Mantzoros CS, Qu D, Frederich RC, Susulic VS, Lowell BB, Maratos-Flier E, Flier JS (1996) Activation of beta3 adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 45:909–914PubMedCrossRefGoogle Scholar
  43. Montrose-Rafizadeh C, Yang H, Pritchette L, Eng J (1998) Distinct activation of GLP-1 receptor by Exendin-4 and GLP-1. Diabetes 47:A192CrossRefGoogle Scholar
  44. Naithani VK, Steffens GJ, Tager HS (1984) Isolation and amino-acid sequence determination of monkey insulin and proinsulin. Hoppe-Seyler’s Z Physiol Chem 365:571–575PubMedCrossRefGoogle Scholar
  45. Ortmeyer HK (1996) Dietary myoinositol results in lower urine glucose and in lower postprandial plasma glucose in obese insulin resistant rhesus monkeys. Obesity Research 4:569–575PubMedGoogle Scholar
  46. Ortmeyer HK, Larner J, Hansen BC (1995) Effects of D-chiroinositol added to a meal on plasma glucose and insulin in hyperinsulinemic rhesus monkeys. Obes Res 3:605S–608SPubMedGoogle Scholar
  47. Ostlund REJ, McGill JB, Herskowitz I, Kipnis DM, Santiago JV, Sherman WS (1993) D-chiro Inositol metabolism in diabetes mellitus. Proc Natl Acad Sci 90:9988–9992PubMedCrossRefGoogle Scholar
  48. Pace N, Kline L, Schachman HK, Harfenist M (1947) Studies on body composition. IV. Use of radioactive hydrogen for measurement in vivo of total body water. J Biol Chem 168:459–469PubMedGoogle Scholar
  49. Rhodes L, Beall M, McGowan E, Tota M (1998) Rhesus macaques treated with human recombinant leptin (hOB) achieve high hOB blood levels, but show no effects on short term food intake. Int J Obesity 22:in press (Abstract # 653)Google Scholar
  50. Schwartz SM, Kemnitz JW (1992) Age-and gender-related changes in body size, adiposity, and endocrine and metabolic parameters in free-ranging rhesus macaques. Am J Physical Anthro 89:109–121CrossRefGoogle Scholar
  51. Schwartz SM, Kemnitz JW, Howard CF (1993) Obesity in free-ranging rhesus macaques. Int J Obes 17:1–10Google Scholar
  52. Snitker S, Foley JE, Ravussin E (1998) Low in vitro adipocyte lipolysis predicts weight gain in non-diabetic Pima Indians. Diabetes 47:A13CrossRefGoogle Scholar
  53. Tang-Christensen M, Havel PJ, Jacobs R, Larsen PJ, Cameron JL (1998) Central administration of human leptin inhibits food intake and activates the sympathetic nervous system in rhesus macaques. Int J Obesity 22:(In press) (Abstract #587)Google Scholar
  54. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devose R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, GG, M, Woolf EA, Monroe CA, Tepper RI (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271Google Scholar
  55. Tavernier G, Barbe P, Galitzky J, Berlan M, Caput D, Lafontan M, Langin D (1996) Expression of β3-adrenoceptors with low lipolytic action in human subcutaneous white adipocytes. J Lipid Res 37:87–97PubMedGoogle Scholar
  56. Viguerie-Bascands N, Bousquet-Melou A, Galitzky J, Larrouy D, Ricquier D, Berlan M, Casteilla L (1996) Evidence for numerous brown adipocytes lacking functional β3-adrenoceptors in fat pads from non-human primates. J Clin Endocrinol Metab 81:368–375PubMedCrossRefGoogle Scholar
  57. Wagner JD, Jayo MJ, Cefalu WT, Hardy VA, Rankin SE, Toombs CF (1996) Recombinant human leptin (rHuLeptin) reduces body weight and body fat and improves insulin sensitivity in non-human primates. Obes Res 4:27SGoogle Scholar
  58. Walike BC, Goodner CJ, Koerke, DJ (1977) Assessment of obesity in pigtailed monkeys (Macaca nemestrina). J Med Primatol 6:151–162PubMedGoogle Scholar
  59. Walike BC, Smith OA (1972) Regulation of food intake during intermittent and continuous cross circulation in monkeys (Macaca mulatto). J Comp Physiol Psychol 80:372–381PubMedCrossRefGoogle Scholar
  60. Walker ML, Schwartz SM, Wilson ME, Musem, PI (1984) Estimation of body fat in female rhesus monkeys. Am J Physical Anthro 63:323–329CrossRefGoogle Scholar
  61. Walston J, Lowe A, Silver K, Yang Y, Bodkin NL, Hansen BC, Shuldiner AR (1997) The β3-adrenergic receptor in the obesity and diabetes prone rhesus monkey is very similar to human and contains arginine at codon 64. Gene 188:207–213PubMedCrossRefGoogle Scholar
  62. Winegar DA, Brown PJ, Wilkison WO, Lewis MC, Orr RJ, Tong WQ, Brown HR, Bodkin NL, Hansen BC (1998) Effects of fenofibrate on lipid parameters in obese rhesus monkeys. The Endocrine Society 216Google Scholar
  63. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • B. C. Hansen

There are no affiliations available

Personalised recommendations