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Sleep, Appetite, and Obesity—What Is the Link?

Prinz

http://medicine.plosjournals.org/perlserv/?request=get-document & doi=10

1371/journal.pmed.0010061

Prinz is research professor, Biobehavioral Nursing and Health

Systems, and adjunct professor, Department of Psychiatry and Behavioral

Sciences, at the University of Washington, Seattle, Washington, United

States of America. E-mail: prinz@...

Published: December 7, 2004

DOI: 10.1371/journal.pmed.0010061

Copyright: © 2004 Prinz. This is an open-access article distributed

under the terms of the Creative Commons Attribution License, which permits

unrestricted use, distribution, and reproduction in any medium, provided the

original work is properly cited.

Abbreviations: BMI, body mass index; SDB, sleep-disordered breathing

Citation: Prinz P (2004) Sleep, Appetite, and Obesity—What Is the Link? PLoS

Med 1(3): e61.

Competing Interests: The author declares that she has no competing interests

There is a well-documented relationship between short sleep duration and

high body mass index (BMI). In the largest study, a survey on sleep duration

and frequency of insomnia in more than 1.1 million participants, increasing

BMI occurred for habitual sleep amounts below 7–8 hours [1]. A recent

prospective study found an association between sleep curtailment and future

weight gain [2]. The mechanism linking short sleep with weight gain is

unknown, but Mignot and colleagues' study in this month's PLoS Medicine [3]

adds to the growing evidence implicating leptin and ghrelin, the two key

opposing hormones involved in appetite regulation.

Hormones That Regulate Appetite

Leptin, a peptide hormone secreted from white adipocytes, is implicated in

the regulation of food intake and energy balance. The hormone acts on the

central nervous system, in particular the hypothalamus, suppressing food

intake and stimulating energy expenditure. Leptin production is primarily

regulated by insulin-induced changes in adipocyte metabolism—its secretion

levels correlate with adipocyte mass and lipid loads.

Leptin promotes inflammation. The hormone provides an interesting link

between obesity and pathophysiological processes such as insulin resistance

and atherosclerosis, and disorders such as autoimmune and cardiovascular

diseases and the metabolic syndrome. Increased serum leptin levels in

obesity and metabolic syndrome support the view that these disorders are in

fact low-grade systemic inflammatory diseases, characterized by increased

concentrations of proinflammatory cytokines like interleukin-6, tumor

necrosis factor-a and leptin. Leptin's proinflammatory role suggests that it

may link energy homeostasis to the immune system [4,5].Ghrelin is a peptide

hormone that stimulates appetite, fat production, and body growth—leading to

increased food intake and body weight. It is secreted into the circulation

from the stomach, but is also synthesised in a number of other tissues,

including the kidney, pituitary, and hypothalamus, suggesting that the

hormone has both distant and local (endocrine and paracrine) effects. These

effects include stimulating the secretion of growth hormone, prolactin, and

adrenocorticotropic hormone, and a diabetogenic effect on carbohydrate

metabolism [6].

The New Study

In this study of 1,024 participants in the population-based Wisconsin Sleep

Cohort Study [7], Mignot and colleagues found that in persons sleeping less

than 8 hours, increased BMI was proportional to decreased sleep [3]. The

researchers also found that shorter sleep times were associated with

increased circulating ghrelin and decreased leptin, a hormonal pattern that

is consistent with decreased energy expenditure and increased appetite and

obesity.

These findings confirm earlier clinical reports on the effects of sleep

deprivation and extend them to include naturalistic sleep in a large,

community-based population. The study provides an exciting addition to the

growing literature showing relationships between sleep curtailment,

metabolic hormones, and metabolic disorders (including obesity). The data

have important implications for our understanding of obesity and related

disorders in the general population, with one caveat: the study population

was enriched with snorers, making the results less applicable to a general

population.

Mignot and colleagues' data are in accord with human and animal studies that

show that experimental curtailment of sleep leads to lower levels of leptin

[8,9,10,11] and increased ghrelin [12]. The new study therefore lends some

support to the interpretation that reduced sleep levels cause the hormonal

changes.

But there is also evidence of opposite effects—that is, that administration

of leptin [13] and ghrelin can alter sleep. Ghrelin administration has been

found to increase non-REM sleep in humans and mice, possibly via its

interactions with the sleep-inducing peptide growth hormone releasing

hormone (GHRH). Ghrelin is an endogenous ligand of the growth hormone

secretagogue receptor, making it a candidate for an endogenous

sleep-promoting factor [14]. Mignot and colleagues' study is congruent with

the idea that inadequate sleep enhances ghrelin secretion, which in turn

acts as an endogenous sleep factor in humans. This is an important new area

of research that could conceivably lead to more physiological sleep aids

than are currently available, with profound implications for improved public

health.

Overall, the available studies suggest the presence of reciprocal

interactions between metabolic hormones and sleep, relationships that are

poorly understood at present. Does sleep interact with metabolic hormones

directly or via intervening factors such as sleep-related breathing

disorders? Patients with obstructive sleep apnea have impaired sleep and

higher ghrelin levels than BMI-matched controls, and treatment with

continuous positive airway pressure reduces ghrelin to control levels [15].

Although sleep-disordered breathing (SDB) was measured in the present study,

the SDB analyses were not shown, making it difficult to evaluate the

influence of SDB on ghrelin and leptin in this population.

There is a clear need for well-controlled, population-based studies that

allow us to examine multiple relevant factors simultaneously. The present

study highlights the importance of shortened sleep in relation to obesity,

leptin, and ghrelin, a good start toward this goal.

Sleep and Public Health

Many other important questions remain, such as the roles that other hormones

cytokines, and SDB play in obesity. Many of the unanswered questions have

important implications for public health. For example, diabetes, visceral

obesity, hypertension, and hyperinsulinemia commonly aggregate together in

large populations, and are considered a “metabolic syndrome” that has been

linked to SDB [16] and to inflammatory disorders [17]. To what extent does

long-term sleep curtailment contribute to these and related public health

issues?

The possible role of sleep restriction in autoimmune and inflammatory

disorders is of particular interest in light of recent findings linking

immune function with ghrelin and leptin. Ghrelin and its receptor are

expressed in human T-lymphocytes, where they can inhibit cytokine activation

including interleukins, tumor necrosis factor-a and leptin [18]. Conversely

leptin stimulates cytokine activation and immune-cell proliferation, an

effect that predisposes to inflammatory conditions [4]. Is it possible, then

that sleep-related changes in leptin and ghrelin influence the development

of metabolic and immune disorders? Can biologically restorative sleep

reverse disease progression? Can biologically restorative sleep be defined

on the basis of metabolic hormone responses? Future research may answer some

of these and other questions, further elucidating the role of sleep in

public health.

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Prinz

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1371/journal.pmed.0010061

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