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. 1998 Jul 15;102(2):340–346. doi: 10.1172/JCI603

Effect of a high-fat diet on food intake and hypothalamic neuropeptide gene expression in streptozotocin diabetes.

M Chavez 1, R J Seeley 1, P J Havel 1, M I Friedman 1, C A Matson 1, S C Woods 1, M W Schwartz 1
PMCID: PMC508892  PMID: 9664075

Abstract

Insulin-deficient diabetic rats are markedly hyperphagic when fed a high-carbohydrate (HC) diet, but normophagic when fed a high-fat (HF) diet. When maintained on a HC diet, diabetic rats also exhibit increased gene expression of the orexigenic peptide neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, and reduced expression of the anorectic peptide corticotropin-releasing hormone (CRH) in the paraventricular nucleus, and these changes are hypothesized to contribute to diabetic hyperphagia. In this experiment we assessed whether the normophagia displayed by HF-fed diabetic rats is associated with the opposite profile of NPY and CRH expression. Our results show that relative to diabetic rats on the HC diet, the diabetic rats on the HF diet exhibited significantly reduced caloric intake (-40%), NPY expression in the arcuate nucleus (-27%), and elevated CRH expression in the paraventricular nucleus (+37%). Insulin and corticosterone, which are known to affect hypothalamic NPY and CRH expression, were not different between these two groups, making it unlikely that they can account for the differences in either feeding behavior or hypothalamic peptide expression. There was a small but significant increase in plasma leptin levels in the diabetic animals maintained on the HF, and large differences in parameters associated with elevated fat oxidation. These observations support the hypothesis that the normalization of food intake observed in diabetic rats consuming a HF diet may in part be mediated by reductions in NPY expression and elevations in CRH expression.

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Selected References

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  1. Akana S. F., Strack A. M., Hanson E. S., Dallman M. F. Regulation of activity in the hypothalamo-pituitary-adrenal axis is integral to a larger hypothalamic system that determines caloric flow. Endocrinology. 1994 Sep;135(3):1125–1134. doi: 10.1210/endo.135.3.8070356. [DOI] [PubMed] [Google Scholar]
  2. Arase K., Shargill N. S., Bray G. A. Effects of corticotropin releasing factor on genetically obese (fatty) rats. Physiol Behav. 1989 Mar;45(3):565–570. doi: 10.1016/0031-9384(89)90074-7. [DOI] [PubMed] [Google Scholar]
  3. Bartness T. J., Rowland N. E. Diet selection and metabolic fuels in three models of diabetes mellitus. Physiol Behav. 1983 Oct;31(4):539–545. doi: 10.1016/0031-9384(83)90079-3. [DOI] [PubMed] [Google Scholar]
  4. Bates M. W. Kinetics of ketone body metabolism in fasted and diabetic rats. Am J Physiol. 1971 Oct;221(4):984–991. doi: 10.1152/ajplegacy.1971.221.4.984. [DOI] [PubMed] [Google Scholar]
  5. Baxter L. C., Schofield P. J. The effects of a high fat diet on chronic streptozotocin-diabetic rats. Diabetologia. 1980 Mar;18(3):239–254. doi: 10.1007/BF00251923. [DOI] [PubMed] [Google Scholar]
  6. Campfield L. A., Smith F. J., Guisez Y., Devos R., Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995 Jul 28;269(5223):546–549. doi: 10.1126/science.7624778. [DOI] [PubMed] [Google Scholar]
  7. Dallman M. F., Strack A. M., Akana S. F., Bradbury M. J., Hanson E. S., Scribner K. A., Smith M. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol. 1993 Oct;14(4):303–347. doi: 10.1006/frne.1993.1010. [DOI] [PubMed] [Google Scholar]
  8. Davis J. D., Wirtshafter D., Asin K. E., Brief D. Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science. 1981 Apr 3;212(4490):81–83. doi: 10.1126/science.7193909. [DOI] [PubMed] [Google Scholar]
  9. Friedman M. I. Hyperphagia in rats with experimental diabetes mellitus: a response to a decreased supply of utilizable fuels. J Comp Physiol Psychol. 1978 Feb;92(1):109–117. doi: 10.1037/h0077431. [DOI] [PubMed] [Google Scholar]
  10. Friedman M. I., Ramirez I., Edens N. K., Granneman J. Food intake in diabetic rats: isolation of primary metabolic effects of fat feeding. Am J Physiol. 1985 Jul;249(1 Pt 2):R44–R51. doi: 10.1152/ajpregu.1985.249.1.R44. [DOI] [PubMed] [Google Scholar]
  11. Giraudo S. Q., Kotz C. M., Grace M. K., Levine A. S., Billington C. J. Rat hypothalamic NPY mRNA and brown fat uncoupling protein mRNA after high-carbohydrate or high-fat diets. Am J Physiol. 1994 May;266(5 Pt 2):R1578–R1583. doi: 10.1152/ajpregu.1994.266.5.R1578. [DOI] [PubMed] [Google Scholar]
  12. Glowa J. R., Gold P. W. Corticotropin releasing hormone produces profound anorexigenic effects in the rhesus monkey. Neuropeptides. 1991 Jan;18(1):55–61. doi: 10.1016/0143-4179(91)90164-e. [DOI] [PubMed] [Google Scholar]
  13. Halaas J. L., Gajiwala K. S., Maffei M., Cohen S. L., Chait B. T., Rabinowitz D., Lallone R. L., Burley S. K., Friedman J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28;269(5223):543–546. doi: 10.1126/science.7624777. [DOI] [PubMed] [Google Scholar]
  14. Havel P. J., Kasim-Karakas S., Mueller W., Johnson P. R., Gingerich R. L., Stern J. S. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J Clin Endocrinol Metab. 1996 Dec;81(12):4406–4413. doi: 10.1210/jcem.81.12.8954050. [DOI] [PubMed] [Google Scholar]
  15. Hawkins R. A., Biebuyck J. F. Ketone bodies are selectively used by individual brain regions. Science. 1979 Jul 20;205(4403):325–327. doi: 10.1126/science.451608. [DOI] [PubMed] [Google Scholar]
  16. Heinrichs S. C., Menzaghi F., Pich E. M., Hauger R. L., Koob G. F. Corticotropin-releasing factor in the paraventricular nucleus modulates feeding induced by neuropeptide Y. Brain Res. 1993 May 14;611(1):18–24. doi: 10.1016/0006-8993(93)91771-j. [DOI] [PubMed] [Google Scholar]
  17. Kanarek R. B., Ho L. Patterns of nutrient selection in rats with streptozotocin-induced diabetes. Physiol Behav. 1984 Apr;32(4):639–645. doi: 10.1016/0031-9384(84)90319-6. [DOI] [PubMed] [Google Scholar]
  18. Krahn D. D., Gosnell B. A., Levine A. S., Morley J. E. Behavioral effects of corticotropin-releasing factor: localization and characterization of central effects. Brain Res. 1988 Mar 8;443(1-2):63–69. doi: 10.1016/0006-8993(88)91598-3. [DOI] [PubMed] [Google Scholar]
  19. Landt M., Gingerich R. L., Havel P. J., Mueller W. M., Schoner B., Hale J. E., Heiman M. L. Radioimmunoassay of rat leptin: sexual dimorphism reversed from humans. Clin Chem. 1998 Mar;44(3):565–570. [PubMed] [Google Scholar]
  20. Langhans W., Scharrer E. Metabolic control of eating. World Rev Nutr Diet. 1992;70:1–67. [PubMed] [Google Scholar]
  21. Leedom L. J., Meehan W. P. The psychoneuroendocrinology of diabetes mellitus in rodents. Psychoneuroendocrinology. 1989;14(4):275–294. doi: 10.1016/0306-4530(89)90030-9. [DOI] [PubMed] [Google Scholar]
  22. Marks J. L., Waite K., Li M. Effects of streptozotocin-induced diabetes mellitus and insulin treatment on neuropeptide Y mRNA in the rat hypothalamus. Diabetologia. 1993 Jun;36(6):497–502. doi: 10.1007/BF02743264. [DOI] [PubMed] [Google Scholar]
  23. Panksepp J., Ritter M. Mathematical analysis of energy regulatory pattens of normal and diabetic rats. J Comp Physiol Psychol. 1975 Nov;89(9):1019–1028. doi: 10.1037/h0077186. [DOI] [PubMed] [Google Scholar]
  24. Pelleymounter M. A., Cullen M. J., Baker M. B., Hecht R., Winters D., Boone T., Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995 Jul 28;269(5223):540–543. doi: 10.1126/science.7624776. [DOI] [PubMed] [Google Scholar]
  25. Ramirez I., Friedman M. I. Dietary hyperphagia in rats: role of fat, carbohydrate, and energy content. Physiol Behav. 1990 Jun;47(6):1157–1163. doi: 10.1016/0031-9384(90)90367-d. [DOI] [PubMed] [Google Scholar]
  26. Ramirez I., Friedman M. I. Food intake and blood fuels after oil consumption: differential effects in normal and diabetic rats. Physiol Behav. 1983 Dec;31(6):847–850. doi: 10.1016/0031-9384(83)90282-2. [DOI] [PubMed] [Google Scholar]
  27. Sahu A., Sninsky C. A., Kalra P. S., Kalra S. P. Neuropeptide-Y concentration in microdissected hypothalamic regions and in vitro release from the medial basal hypothalamus-preoptic area of streptozotocin-diabetic rats with and without insulin substitution therapy. Endocrinology. 1990 Jan;126(1):192–198. doi: 10.1210/endo-126-1-192. [DOI] [PubMed] [Google Scholar]
  28. Sahu A., Sninsky C. A., Phelps C. P., Dube M. G., Kalra P. S., Kalra S. P. Neuropeptide Y release from the paraventricular nucleus increases in association with hyperphagia in streptozotocin-induced diabetic rats. Endocrinology. 1992 Dec;131(6):2979–2985. doi: 10.1210/endo.131.6.1446635. [DOI] [PubMed] [Google Scholar]
  29. Schwartz M. W., Baskin D. G., Bukowski T. R., Kuijper J. L., Foster D., Lasser G., Prunkard D. E., Porte D., Jr, Woods S. C., Seeley R. J. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 1996 Apr;45(4):531–535. doi: 10.2337/diab.45.4.531. [DOI] [PubMed] [Google Scholar]
  30. 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. 1996 Sep 1;98(5):1101–1106. doi: 10.1172/JCI118891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Schwartz M. W., Sipols A. J., Marks J. L., Sanacora G., White J. D., Scheurink A., Kahn S. E., Baskin D. G., Woods S. C., Figlewicz D. P. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology. 1992 Jun;130(6):3608–3616. doi: 10.1210/endo.130.6.1597158. [DOI] [PubMed] [Google Scholar]
  32. Seeley R. J., van Dijk G., Campfield L. A., Smith F. J., Burn P., Nelligan J. A., Bell S. M., Baskin D. G., Woods S. C., Schwartz M. W. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm Metab Res. 1996 Dec;28(12):664–668. doi: 10.1055/s-2007-979874. [DOI] [PubMed] [Google Scholar]
  33. Sipols A. J., Baskin D. G., Schwartz M. W. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes. 1995 Feb;44(2):147–151. doi: 10.2337/diab.44.2.147. [DOI] [PubMed] [Google Scholar]
  34. Stanley B. G., Kyrkouli S. E., Lampert S., Leibowitz S. F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides. 1986 Nov-Dec;7(6):1189–1192. doi: 10.1016/0196-9781(86)90149-x. [DOI] [PubMed] [Google Scholar]
  35. Stanley B. G., Leibowitz S. F. Neuropeptide Y injected in the paraventricular hypothalamus: a powerful stimulant of feeding behavior. Proc Natl Acad Sci U S A. 1985 Jun;82(11):3940–3943. doi: 10.1073/pnas.82.11.3940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tordoff M. G., Tepper B. J., Friedman M. I. Food flavor preferences produced by drinking glucose and oil in normal and diabetic rats: evidence for conditioning based on fuel oxidation. Physiol Behav. 1987;41(5):481–487. doi: 10.1016/0031-9384(87)90084-9. [DOI] [PubMed] [Google Scholar]
  37. Velasco A., Huerta I., Marin B. Plasma corticosterone, motor activity and metabolic circadian patterns in streptozotocin-induced diabetic rats. Chronobiol Int. 1988;5(2):127–135. doi: 10.3109/07420528809079553. [DOI] [PubMed] [Google Scholar]
  38. WIELAND O. Eine enzymatische Methode zur Bestimmung von Glycerin. Biochem Z. 1957;329(4):313–319. [PubMed] [Google Scholar]
  39. Weigle D. S., Bukowski T. R., Foster D. C., Holderman S., Kramer J. M., Lasser G., Lofton-Day C. E., Prunkard D. E., Raymond C., Kuijper J. L. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse. J Clin Invest. 1995 Oct;96(4):2065–2070. doi: 10.1172/JCI118254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. White J. D., Olchovsky D., Kershaw M., Berelowitz M. Increased hypothalamic content of preproneuropeptide-Y messenger ribonucleic acid in streptozotocin-diabetic rats. Endocrinology. 1990 Feb;126(2):765–772. doi: 10.1210/endo-126-2-765. [DOI] [PubMed] [Google Scholar]
  41. Williams G., Gill J. S., Lee Y. C., Cardoso H. M., Okpere B. E., Bloom S. R. Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozocin-induced diabetic rats. Diabetes. 1989 Mar;38(3):321–327. doi: 10.2337/diab.38.3.321. [DOI] [PubMed] [Google Scholar]
  42. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

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