AJP - Regu Information on EB 2010
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 290: R892-R893, 2006; doi:10.1152/ajpregu.00845.2005
0363-6119/06 $8.00
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lydic, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lydic, R.

EDITORIAL FOCUS

CALL FOR PAPERS
Metabolic Syndrome

Sleep disruption is related to allelic variation in the ob gene

Ralph Lydic

Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan

RECENT ADVANCES MAKE IT EASY to forget that investigators in the biological sciences once shunned the study of behavior. Today, students at research-intensive universities are imbued with an interdisciplinary perspective (9) that regards behavior as a higher-level expression of cellular and molecular physiology. In this issue of the American Journal of Physiology-Regulatory, Integrative, and Comparative Physiology, a paper by Laposky et al. (12a) titled "Altered Sleep Regulation in Leptin- Deficient Mice" exemplifies the natural unification of behavior and physiology. Sleep is a behavioral state that significantly alters autonomic, metabolic, and sensory-motor regulation. Sleep-dependent changes in regulatory physiology are so pronounced that behavioral states can provide an organizational structure for teaching regulatory physiology (32). The Laposky et al. (12a) paper also provides a striking example of how the interpretation of preclinical data from mice can offer mechanistic insights of potential clinical relevance. Specifically, their results have been triangulated to consider the relationship between obesity and sleep, obesity and energy expenditure, and the utility of the mouse as a tool for understanding human physiology and pathophysiology.

Obesity is a disease with many associated comorbidities (6). In the United States and United Kingdom, the number of individuals who are obese has reached epidemic proportions (1, 5). The worldwide prevalence of obesity in children indicates that obesity-related diseases and health care costs will be a problem for many years (35). The time course of the obesity epidemic has outpaced obesity research and treatment (15). A report from the United States National Task Force on the Prevention and Treatment of Obesity (19) begins by noting that as recently as 1998, the health risks of obesity were not fully appreciated. The causes of obesity are multifactorial and the variance accounted for by each putative cause remains to be quantified.

Brain regions regulating sleep overlap with areas of brain that regulate appetite (13). The ob gene is expressed by fat cells that produce leptin, and this peptide, in turn, modulates food intake (26). By unknown central mechanisms, sleep restriction and deprivation are related to leptin and insulin resistance (24, 25). Obese individuals are at risk for developing obstructive sleep apnea (OSA) (19), and OSA patients have greater serum levels of leptin (12). Total sleep deprivation decreases the diurnal rhythm of leptin (17). Recent human data indicate that sleep loss is a risk factor for developing insulin resistance and type 2 diabetes (23). Obesity is associated with short sleep duration, and short sleep duration is a risk factor for diabetes and heart disease (10). There is support for the hypothesis that OSA is part of a feed-forward metabolic syndrome, in which visceral obesity causes insulin resistance and elevates inflammatory cytokines (34). A transcription factor (Clock) has been identified in mutant mice that alters the circadian distribution of sleep and may also contribute to obesity and metabolic syndrome (33).

Consistent with previous data (7), Laposky et al. (12a) show that obese mice are sedentary. Locomotor activity contributes to the regulation of core body temperature in mice, and Laposky et al. report that obese mice have a reduced body temperature in all sleep-wake states compared with C57BL/6J (B6) mice. This too is a significant finding in view of the fact that heart rate and mean arterial pressure are significantly altered in B6 mice by reduced caloric intake and exposure to mild cold stress (36). The rodent data are in line with evidence considering fat to be an endocrine organ, from which adipocyte-derived cytokines modulate the balance between energy intake and energy expenditure (2). Rats bred for low aerobic capacity score high on risk factors for the metabolic syndrome (37). In contrast, exercise capacity is a predictor of human mortality (18) and exercise can extend human longevity (8). Even modest decreases in weight have been shown to cause a decrease in sleep-disordered breathing (20).

Finally, the well-designed study by Laposky et al. (12a) contributes to the growing evidence that mice provide a powerful model of human disease (3, 4, 27). In 2002, the mouse genome was first published, revealing a 99% homology with the human genome (16). This remarkable homology helped promote the Trans-NIH Mouse Initiative (www.nih.gov/science/models/mouse/) and prompted the description of mice on the National Institutes of Health genome Web page, as "the most important animal model in biomedical research" (http://www.genome.gov/10005831). Years before B6 mice were used to study breathing during sleep (14, 28), obese mice were shown to be a valuable model of the altered breathing observed in obese humans (29–31). Leptin-deficient mice were discovered as a spontaneous mutation of the ob gene in B6 mice (11). Leptin-deficient mice are obese, hyperphagic, and sedentary, compared with normal B6 mice. All models have a limited domain of applicability, and the search for perfect identity between human and animal or pharmacological (14) models is a fool's errand. Differences between a model and the system being modeled are anticipated. For example, in obese mice, the absence of leptin does not lead to upper airway collapse during sleep (21). This difference does not negate the strong genetic modulation of sleep and obesity (22). When congenic lines, such as B6 and ob mice exhibit a significant difference in phenotype, and a single difference in genotype, it is parsimonious to infer that the missing or altered gene contributes to the differences in phenotype (7). By combining a detailed phenotyping of sleep behavior, locomotion, and body temperature, the paper by Laposky et al. (12a) suggests that deletion of the ob gene and/or gene product contributes to obesity and disrupts the temporal organization of sleep.

GRANTS

This work was supported by HL-57120, HL-40881, and HL-65272 and by the Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan.

FOOTNOTES


Address for reprint requests and other correspondence: R. Lydic, Dept. of Anesthesiology, the Univ. of Michigan, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0615 (e-mail: rlydic{at}umich.edu)

REFERENCES

  1. Abelson P and Kennedy D. The obesity epidemic (Editorial). Science 304: 1413, 2004.[Abstract]
  2. Berggren JR, Hulver MW, and Houmard JA. Fat as an endocrine organ: influence of exercise. J Appl Physiol 99: 757–764, 2005.[Abstract/Free Full Text]
  3. Bockamp E, Maringer M, Spangenberg C, Fees S, Fraser S, Eshkind L, Oesch F, and Zabel B. Of mice and models: improved animal models for biomedical research. Physiol Genomics 11: 115–132, 2002.[Abstract/Free Full Text]
  4. Bogue C. Functional genomics in the mouse: powerful techniques for unraveling the basis of human development and disease. J Appl Physiol 94: 2502–2509, 2003.[Abstract/Free Full Text]
  5. Campbell I. The obesity epidemic: can we turn the tide? Heart 89: ii22–ii24, 2003.[Abstract/Free Full Text]
  6. Conway B and Rene A. Obesity as a disease: no lightweight matter. Obes Rev 5: 145–151, 2004.[CrossRef][Medline]
  7. Douglas CL, Bowman GN, Baghdoyan HA, and Lydic R. C57BL/6J and B6.V-LEPOB mice differ in the cholinergic modulation of sleep and breathing. J Appl Physiol 98: 918–929, 2005.[Abstract/Free Full Text]
  8. Franco OH, de Laet C, Peeters A, Jonker J, Mackenbach J, and Nusselder W. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med 165: 2355–2360, 2005.[Abstract/Free Full Text]
  9. Gonzales C. Undergraduate research, graduate mentoring, and the university's mission. Science 293: 1624–1626, 2001.[Abstract/Free Full Text]
  10. Hasler G, Buysse DJ, Klaghofer R, Gamma A, Ajdacic V, Eich D, Rossler W, and Angst J. The association between short sleep duration and obesity in young adults: a 13-year prospective study. Sleep 27: 661–666, 2004.[Web of Science][Medline]
  11. Ingalls AM, Dickie MM, and Snell GD. Obese, a new mutation in the house mouse. J Hered 41: 317–318, 1950.[Free Full Text]
  12. Ip MSM, Lam KSL, Ho C, Tsang KWT, and Lam W. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 118: 580–586, 2000.[CrossRef][Web of Science][Medline]
  13. Laposky AD, Shelton J, Bass J, Dugovic C, Perrino N, and Turek FW. Altered sleep regulation in leptin-deficient mice. Am J Physiol Regul Integr Comp Physiol 290: R894–R903, 2006.[Abstract/Free Full Text]
  14. Lydic R and Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 103: 1268–1295, 2005.[CrossRef][Web of Science][Medline]
  15. Lydic R, Douglas CL, and Baghdoyan HA. Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing. Sleep 25: 835–841, 2002.[Web of Science][Medline]
  16. Manson JE, Skerrett PJ, Greenland P, and VanItallie TB. The escalating pandemics of obesity and sedentary lifestyle. Arch Intern Med 164: 249–258, 2004.[Abstract/Free Full Text]
  17. Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420: 520–562, 2002.[CrossRef][Medline]
  18. Mullington JM, Chan JL, Van Dongen HPA, Szuba MP, Samaras J, Price NJ, Meier-Ewert HK, Dinges DF, and Mantzoros CS. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol 15: 851–854, 2003.[CrossRef][Web of Science][Medline]
  19. Myers J, Prakash M, Froelicher V, Do D, Partington S, and Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med 346: 793–801, 2002.[Abstract/Free Full Text]
  20. National Task Force Report. Overweight, obesity, and health risks. Arch Intern Med 160: 898–904, 2000.[Abstract/Free Full Text]
  21. Newman AB, Foster G, Givelber R, Nieto FJ, Redline S, and Young T. Progression and regression of sleep-disordered breathing with changes in weight. Arch Intern Med 165: 2408–2413, 2005.[Abstract/Free Full Text]
  22. O'Donnell C, Tankersley CG, Polotsky VY, Schwartz AR, and Smith PL. Leptin, obesity, and respiratory function. Respir Physiol 119: 173–180, 2000.
  23. Patel SR. Shared genetic risk factors for obstructive sleep apnea and obesity. J Appl Physiol 99: 1600–1606, 2005.[Abstract/Free Full Text]
  24. Spiegel K, Knuston K, Leproult R, Tasali E, and Van Cauter E. Sleep loss: a novel risk factor for insulin resistance and type 2 diabetes. J Appl Physiol 99: 2008–2019, 2005.[Abstract/Free Full Text]
  25. Spiegel K, Leproult R, L'Hermite-Baleriaux M, Copinschi G, Penev PD, and Van Cauter E. Leptin levels are dependent on sleep duration: relationship with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 89: 5762–5771, 2004.[Abstract/Free Full Text]
  26. Spiegel K, Leproult R, and Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 354: 1435–1439, 1999.[CrossRef][Web of Science][Medline]
  27. Stanley S, Wynne K, McGowan B, and Bloom S. Hormonal regulation of food intake. Physiol Rev 85: 1131–1158, 2005.[Abstract/Free Full Text]
  28. Svenson KL, Bogue MA, and Peters LL. Identifying new mouse models of cardiovascular disease: a review of high-throughput screens of mutagenized and inbred strains. J Appl Physiol 94: 1650–1659, 2003.[Abstract/Free Full Text]
  29. Tagaito Y, Polotsky VY, Campen MJ, Wilson JA, Balbir A, Smith PL, Schwartz AR, and O'Donnell CP. A model of sleep-disordered breathing in the C57BL/6J mouse. J Appl Physiol 91: 2758–2766, 2001.[Abstract/Free Full Text]
  30. Tankersley CG. Genetic control of ventilation: what are we learning from murine models? Curr Opin Pulm Med 5: 344–348, 1999.[CrossRef][Medline]
  31. Tankersley CG, Kleeberger S, Russ B, Schwartz A, and Smith P. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 81: 716–723, 1996.[Abstract/Free Full Text]
  32. Tankersley CG, O'Donnell C, Daood MJ, Watchko JF, Mitzner W, Schwartz A, and Smith P. Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol 85: 2261–2269, 1998.[Abstract/Free Full Text]
  33. Thompson SR, Ackermann U, and Horner RL. Sleep as a teaching tool for integrating respiratory physiology and motor control. Adv Physiol Educ 25: 29–44, 2001.[Web of Science]
  34. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, and Bass F. Obesity and metabolic syndrome in circadian CLOCK mutant mice. Science 308: 1043–1045, 2005.[Abstract/Free Full Text]
  35. Vgontzas AN, Bixler EO, and Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 9: 211–224, 2005.[CrossRef][Web of Science][Medline]
  36. Wang G and Dietz WH. Economic burden of obesity in youths aged 6 to 17 years: 1979–1999. Pediatrics 109: 1–6, 2002.[Abstract/Free Full Text]
  37. Williams TD, Chambers JB, Henderson RP, Rashotte ME, and Overton JM. Cardiovascular responses to caloric restriction and thermoneutrality in C57BL/6J mice. Am J Physiol Regul Integr Comp Physiol 282: R1459–R1467, 2002.[Abstract/Free Full Text]
  38. Wisloff U, Najjar SM, Ellingsen O, Haram PM, Swoap S, Al-Share Q, Fernstrom M, Rezaei K, Lee JL, Koch LG, and Britton SL. Cardiovascular risk factors emerge after artificial selection for low aerobic capacity. Science 307: 418–420, 2005.[Abstract/Free Full Text]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lydic, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lydic, R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.