Circadian Neuroendocrine-Immune Aspects of Feeding Behavior: Lessons from Calorie-Restricted or High-Fat-Fed Rats

  • Ana I. Esquifino
  • Daniel P. Cardinali


The circadian clock is one of the most indispensable biological functions for living organisms that acts like a multifunctional timer to adjust the homeostatic system, including sleep and wakefulness, hormonal secretions, immune function, and various other bodily functions. In mammals, the circadian system is composed of many individual, tissue-specific cellular clocks. To generate coherent physiological and behavioral responses, the phases of this multitude of cellular clocks are orchestrated by a master circadian pacemaker residing in the suprachiasmatic nuclei of the hypothalamus. At a molecular level, circadian clocks are based on clock genes, some of which encode proteins able to feedback and inhibit their own transcription. These cellular oscillators consist of interlocked transcriptional and posttranslational feedback loops that involve a small number of core clock genes (about 12 genes identified currently). Virtually all neuroendocrine and immunological variables investigated in animals and humans display biological periodicity. Circadian rhythmicity is revealed for every hormone in circulation as well as for circulating immune cells, lymphocyte metabolism and transformability, cytokines, receptors, and adhesion molecules. This review discusses the circadian disruption of hormone release and immune-related mechanisms by calorie restriction and a high fat diet in rats. In every case the experimental manipulation used has perturbed the temporal organization by affecting the shape and amplitude of a rhythm or by modifying the intrinsic oscillatory mechanism itself.


Luteinizing Hormone Calorie Restriction Circadian Clock Clock Gene Plasma ACTH 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.





Follicle-stimulating hormone


Growth hormone






Luteinizing hormone


Monocyte chemoattractant protein-1


Plasminogen activator inhibitor-1


Suprachiasmatic nucleus


Tumor necrosis factor-α


Thyroid-stimulating hormone



Work in authors’ laboratories was supported in part by DGES, Spain, Agencia Nacional de Promoción Científica y Tecnológica, Argentina, the University of Buenos Aires and CONICET, Argentina.


  1. Pandi-Perumal SP, Cardinali DP, Chrousos GP. Neuroimmunology of sleep. New York: Springer Science + Business Media, LLC; 2007.CrossRefGoogle Scholar
  2. Antic V, Van Vliet BN, Montani JP. Loss of nocturnal dipping of blood pressure and heart rate in obesity-induced hypertension in rabbits. Auton Neurosci. 2001;90:152–7.PubMedCrossRefGoogle Scholar
  3. Bartness TJ, Demas GE, Song CK. Seasonal changes in adiposity: the roles of the photoperiod, melatonin and other hormones, and sympathetic nervous system. Exp Biol Med (Maywood). 2002;227:363–76.Google Scholar
  4. Cano P, Cardinali DP, Fernandez P, Reyes Toso C, Esquifino AI. 24-hour rhythms of splenic mitogenic responses, lymphocyte subset populations and interferon ã release after calorie restriction or social isolation of rats. Biol Rhythm Res. 2006;37:255–63.CrossRefGoogle Scholar
  5. Cano P, Carreras LO, Ríos-Lugo MP, Fernández-Mateos MP, Reyes MP, Esquifino AI. Effect of a high-fat diet on 24-hour pattern of circulating adipocytokines in rats. Obesity. 2009;17:1866–71.PubMedCrossRefGoogle Scholar
  6. Cano P, Jimenez-Ortega V, Larrad A, Reyes Toso CF, Cardinali DP, Esquifino AI. Effect of a high-fat diet on 24-hour pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid stimulating hormone and glucose, and pineal melatonin content, in rats. Endocrine. 2008;33:118–25.PubMedCrossRefGoogle Scholar
  7. Cano P, Poliandri AH, Jimenez V, Cardinali DP, Esquifino AI. Cadmium-induced changes in Per 1 and Per 2 gene expression in rat hypothalamus and anterior pituitary: Effect of melatonin. Toxicol Lett. 2007;172(3):131–6.PubMedCrossRefGoogle Scholar
  8. Carroll JF, Thaden JJ, Wright AM, Strange T. Loss of diurnal rhythms of blood pressure and heart rate caused by high-fat feeding. Am J Hypertens. 2005;18:1320–6.PubMedCrossRefGoogle Scholar
  9. Chacon F, Cano P, Jimenez V, Cardinali DP, Marcos A, Esquifino AI. 24-hour changes in circulating prolactin, follicle-stimulating hormone, luteinizing hormone and testosterone in young male rats subjected to calorie restriction. Chronobiol Int. 2004;21:393–404.PubMedCrossRefGoogle Scholar
  10. Chacon F, Esquifino AI, Perelló M, Cardinali DP, Spinedi E, Alvarez MP. 24-hour changes in ACTH, corticosterone, growth hormone and leptin levels in young male rats subjected to calorie restriction. Chronobiol Int. 2005;22:253–65.PubMedCrossRefGoogle Scholar
  11. Chen A, Mumick S, Zhang C, Lamb J, Dai H, Weingarth D, et al. Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res. 2005;13:1311–20.PubMedCrossRefGoogle Scholar
  12. Chen D, Wang MW. Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab. 2005;7:307–17.PubMedCrossRefGoogle Scholar
  13. Cutolo M, Sulli A, Pizzorni C, Secchi ME, Soldano S, Seriolo B, et al. Circadian rhythms: glucocorticoids and arthritis. Ann NY Acad Sci. 2006;1069:289–99.PubMedCrossRefGoogle Scholar
  14. Elin RJ, Winters SJ. Current controversies in testosterone testing: aging and obesity. Clin Lab Med. 2004;24:119–39.PubMedCrossRefGoogle Scholar
  15. Esquifino AI, Cano P, Jimenez V, Cutrera RA, Cardinali DP. Experimental allergic encephalomyelitis in male Lewis rats subjected to calorie restriction. J Physiol Biochem. 2004a;60:245–52.PubMedCrossRefGoogle Scholar
  16. Esquifino AI, Cano P, Jimenez-Ortega V, Fernández-Mateos MP, Cardinali DP. Immune response after experimental allergic encephalomyelitis in rats subjected to calorie restriction. J Neuroinflammation. 2007;4(1):6.PubMedCrossRefGoogle Scholar
  17. Esquifino AI, Chacon F, Cano P, Marcos A, Cutrera RA, Cardinali DP. 24-hour rhythms of mitogenic responses, lymphocyte subset populations and amino acid content in submaxillary lymph nodes of growin male rats subjected to calorie restriction. J Neuroimmunol. 2004b;156:66–73.PubMedCrossRefGoogle Scholar
  18. Filipski E, King VM, Etienne MC, Li X, Claustrat B, Granda TG, et al. Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice. Am J Physiol Regul Integr Comp Physiol. 2004;287:R844–51.PubMedCrossRefGoogle Scholar
  19. Froy O. The relationship between nutrition and circadian rhythms in mammals. Front Neuroendocrinol. 2007;28:61–71.PubMedCrossRefGoogle Scholar
  20. Glueck CJ, Levy RI, Fredrickson DS. Immunoreactive insulin, glucose tolerance, and carbohydrate inducibility in types II, 3, IV, and V hyperlipoproteinemia. Diabetes. 1969;18:739–47.PubMedGoogle Scholar
  21. Gromadzka-Ostrowska J, Przepiorka M, Romanowicz K. Influence of dietary fatty acids composition, level of dietary fat and feeding period on some parameters of androgen metabolism in male rats. Reprod Biol. 2002;2:277–93.PubMedGoogle Scholar
  22. Guest CB, Park MJ, Johnson DR, Freund GG. The implication of proinflammatory cytokines in type 2 diabetes. Front Biosci. 2008;13:5187–94.PubMedCrossRefGoogle Scholar
  23. Hastings MH, Reddy AB, Maywood ES. A clockwork web: circadian timing in brain and periphery, in health and disease. Nat Rev Neurosci. 2003;4:649–61.PubMedCrossRefGoogle Scholar
  24. Holvoet P. Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. Verh K Acad Geneeskd Belg. 2008;70:193–219.PubMedGoogle Scholar
  25. Ishihara Y, White CL, Kageyama H, Kageyama A, York DA, Bray GA. Effects of diet and time of the day on serum and CSF leptin levels in Osborne-Mendel and S5B/Pl rats. Obes Res. 2004;12:1067–76.PubMedCrossRefGoogle Scholar
  26. Ladizesky MG, Boggio V, Albornoz LE, Castrillón P, Mautalen CA, Cardinali DP. Melatonin increases oestradiol-induced bone formation in ovariectomized rats. J Pineal Res. 2003;34:143–51.PubMedCrossRefGoogle Scholar
  27. Lu ZH, Mu YM, Wang BA, Li XL, Lu JM, Li JY, et al. Saturated free fatty acids, palmitic acid and stearic acid, induce apoptosis by stimulation of ceramide generation in rat testicular Leydig cell. Biochem Biophys Res Commun. 2003;303:1002–7.PubMedCrossRefGoogle Scholar
  28. Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol. 2000;35:299–305.PubMedCrossRefGoogle Scholar
  29. Moore-Ede MC. Physiology of the circadian timing system: predictive versus reactive homeostasis. Am J Physiol. 1986;250:R737–52.PubMedGoogle Scholar
  30. Pahlavani MA. Influence of caloric restriction on aging immune system. J Nutr Health Aging. 2004;8:38–47.PubMedGoogle Scholar
  31. Phillips LK, Prins JB. The link between abdominal obesity and the metabolic syndrome. Curr Hypertens Rep. 2008;10:156–64.PubMedCrossRefGoogle Scholar
  32. Prunet-Marcassus B, Desbazeille M, Bros A, Louche K, Delagrange P, Renard P, et al. Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity. Endocrinology. 2003;144:5347–52.PubMedCrossRefGoogle Scholar
  33. Raskind MA, Burke BL, Crites NJ, Tapp AM, Rasmussen DD. Olanzapine-induced weight gain and increased visceral adiposity is blocked by melatonin replacement therapy in rats. Neuropsychopharmacology. 2006;32:284–8.PubMedCrossRefGoogle Scholar
  34. Rasmussen DD, Mitton DR, Larsen SA, Yellon SM. Aging-dependent changes in the effect of daily melatonin supplementation on rat metabolic and behavioral responses. J Pineal Res. 2001;31:89–94.PubMedCrossRefGoogle Scholar
  35. Roth GS, Ingram DK, Lane MA. Calorie restriction in primates: Will it work and how will we know? J Am Geriatr Soc. 1999;47:896–903.PubMedGoogle Scholar
  36. Sanchez-Mateos S, Alonso-Gonzalez C, Gonzalez A, Martinez-Campa CM, Mediavilla MD, Cos S, et al. Melatonin and estradiol effects on food intake, body weight, and leptin in ovariectomized rats. Maturitas. 2007;58:91–101.PubMedCrossRefGoogle Scholar
  37. Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA. 2003;100:7265–70.PubMedCrossRefGoogle Scholar
  38. Sheng T, Yang K. Adiponectin and its association with insulin resistance and type 2 diabetes. J Genet Genomics. 2008;35:321–6.PubMedCrossRefGoogle Scholar
  39. Tannenbaum BM, Brindley DN, Tannenbaum GS, Dallman MF, McArthur MD, Meaney MJ. High-fat feeding alters both basal and stress-induced hypothalamic-pituitary-adrenal activity in the rat. Am J Physiol. 1997;273:E1168–77.PubMedGoogle Scholar
  40. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222–31.PubMedCrossRefGoogle Scholar
  41. Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol. 2007;275:43–61.PubMedCrossRefGoogle Scholar
  42. Waki H, Tontonoz P. Endocrine functions of adipose tissue. Annu Rev Pathol. 2007;2:31–56.PubMedCrossRefGoogle Scholar
  43. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–808.PubMedGoogle Scholar
  44. Winters SJ, Wang C, Abdelrahaman E, Hadeed V, Dyky MA, Brufsky A. Inhibin-B levels in healthy young adult men and prepubertal boys: is obesity the cause for the contemporary decline in sperm count because of fewer Sertoli cells? J Androl. 2006;27:560–4.PubMedCrossRefGoogle Scholar
  45. Yanagihara H, Ando H, Hayashi Y, Obi Y, Fujimura A. High-fat feeding exerts minimal effects on rhythmic mRNA expression of clock genes in mouse peripheral tissues. Chronobiol Int. 2006;23:905–14.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Departamento de Bioquímica y Biología Molecular IIIUniversidad ComplutenseMadridSpain

Personalised recommendations