Obesity and sleep disturbances: The “chicken or the egg” question

  • Author Footnotes
    # All the authors equally contributed to the manuscript.
    Gabriel Dias Rodrigues
    Footnotes
    # All the authors equally contributed to the manuscript.
    Affiliations
    Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, 24210-130, Brazil

    Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
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  • Author Footnotes
    # All the authors equally contributed to the manuscript.
    Elisa M. Fiorelli
    Footnotes
    # All the authors equally contributed to the manuscript.
    Affiliations
    Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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  • Author Footnotes
    # All the authors equally contributed to the manuscript.
    Ludovico Furlan
    Footnotes
    # All the authors equally contributed to the manuscript.
    Affiliations
    Department of Emergency Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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  • Nicola Montano
    Correspondence
    Corresponding author.
    Affiliations
    Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy

    Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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  • Eleonora Tobaldini
    Affiliations
    Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy

    Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
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  • Author Footnotes
    # All the authors equally contributed to the manuscript.

      Highlights

      • Obesity and sleep disturbances are linked by a bi-directional causal-effect relation.
      • Sleep disturbances increase the risk of obesity and metabolic syndrome.
      • Obesity is a risk factor for several sleep disorders (such as Obstructive Sleep Apnea).
      • It is mandatory to investigate possible sleep disorders in obese patients.

      Abstract

      Obesity and sleep disturbances are common conditions in modern societies and accumulating evidence support a close bidirectional causal relationship between these two conditions.
      Indeed, from one side sleep loss seems to affect energy intake and expenditure through its direct effects on hormone-mediated sensations of satiety and hunger and through the influence on hedonic and psychological aspects of food consumption. Sleep deprived patients have been shown to experiment excessive daytime sleepiness, fatigue, and tiredness that, in a vicious circle, enhances physical inactivity and weight gain. On the other side, obesity is a well-known risk factor for several sleep disorders. This narrative review will discuss the main pathophysiological mechanisms that link sleep loss to obesity and metabolic syndrome with particular attention to the three most common sleep disorders (insomnia, obstructive sleep apnoea syndrome, restless leg syndrome).

      1. Introduction

      Since 1980 obesity has seen a rapid increase in global prevalence, that has almost doubled in many countries and nowadays affects more than 12% of the general population [
      The GBD
      Obesity collaborators (2017) health effects of overweight and obesity in 195 countries over 25 years.
      ]. Interestingly, the rapid rise in obesity prevalence in the last decades parallels a significant reduction in restorative sleep and an increase in the prevalence of sleep disturbances [
      • Matsumoto T
      • Chin K
      Prevalence of sleep disturbances: sleep disordered breathing, short sleep duration, and non-restorative sleep.
      ,
      • Cizza G
      • Requena M
      • Galli G
      • de Jonge L
      Chronic sleep deprivation and seasonality: implications for the obesity epidemic.
      ].
      These two syndromes probably share common risk factors, but it is likely that a bidirectional causal relationship exists among them. Indeed, other than the behavioural and dietary factors that favour obesity, the poor quality and the sleep loss could also be related to weight gain and obesity. Sleep disordered breathing (SDB) are frequent in population with obesity and sleep insufficiency and may predispose to weight gain, through the creation of an obesogenic environment, a direct effect on appetite hormones and also a significant reduction of daily physical activity [
      • Cizza G
      • Requena M
      • Galli G
      • de Jonge L
      Chronic sleep deprivation and seasonality: implications for the obesity epidemic.
      ,
      • Magee CA
      • Huang X-F
      • Iverson DC
      • Caputi P
      Examining the pathways linking chronic sleep restriction to obesity.
      ]. On the other hand, obesity has been linked, as a predisposing factor, to many sleep disorders [
      • Wolk R
      • Shamsuzzaman ASM
      • Somers VK
      Obesity, sleep apnea, and hypertension.
      ,
      • Baran RT
      • Atar M
      • Pirgon Ö
      • et al.
      Restless legs syndrome and poor sleep quality in obese children and adolescents.
      ,
      • Brum MCB
      • Dantas Filho FF
      • Schnorr CC
      • et al.
      Night shift work, short sleep and obesity.
      ].
      Understanding the link between obesity and sleep loss is important to better treat these conditions, that have been both associated to an increase in cardiovascular risk [
      • Tobaldini E
      • Fiorelli EM
      • Solbiati M
      • et al.
      Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence.
      ,
      • Blüher M
      Obesity: global epidemiology and pathogenesis.
      ,
      • Montano N
      • Fiorelli E
      • Tobaldini E
      Sleep duration and the heart: I sleep, therefore I beat.
      ].

      2. Short sleep and obesity: Physiopathological aspects

      The sleep-wake state is determined by complex humoral, neurochemical and neuronal networks. Sleep is a dynamic process composed by four to six sleep cycles in a normal night. Usually, a cycle is composed by the alternance of three different non-rapid eye movement (NREM) sleep stages (N1: sleep onset; N2: light sleep; N3: deep sleep or slow-wave sleep) and the rapid eye movement (REM) one [
      • Berry R
      • Quan S
      • Abreu AR
      for the American Academy of Sleep Medicine
      The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications.
      ]. Each stage has a distinct physiologic regulation and is essential to good health. Sleep stages can be altered by several factors such as age, recent sleep patterns, alcohol, and sleep disorders.
      Sleep duration and sleep quality both contribute to guarantee restorative sleeping. The National Sleep Foundation recommends between 10 and 13 hours per night of sleep for pre-schoolers, 9–11 hours for school-aged children, and 8–10 hours for adolescents and 7-9 hours for adult to improve health and well-being [
      • Watson N
      • Badr M
      • Belenky G
      Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society.
      ]. However, we sleep less than we really need [
      • Liu Y
      • Wheaton AG
      • Chapman DP
      • et al.
      Prevalence of healthy sleep duration among adults — United States, 2014.
      ]. Various terms describing “short sleep” time exist: according to Grandner et al. short sleep duration is defined as a habitual sleep time of ≤6 h, sleep deprivation as acute sleep curtailment in the laboratory setting, and sleep loss as a decrease in sleep time relative to previous sleep time [
      • Grandner MA
      • Patel NP
      • Gehrman PR
      • et al.
      Problems associated with short sleep: bridging the gap between laboratory and epidemiological studies.
      ]. More generally, the term “sleep insufficiency” is used when a reduction in sleep time is associated with negative outcomes [
      • Grandner MA
      • Patel NP
      • Gehrman PR
      • et al.
      Problems associated with short sleep: bridging the gap between laboratory and epidemiological studies.
      ]. In fact, although several studies have shown that even acute sleep deprivation can have direct effects on biological events [
      • Irwin MR
      • Wang M
      • Campomayor CO
      • et al.
      Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation.
      ,
      • Sauvet F
      • Leftheriotis G
      • Gomez-Merino D
      • et al.
      Effect of acute sleep deprivation on vascular function in healthy subjects.
      ], it is reasonable to believe that negative cardiovascular and metabolic outcomes are mainly favoured by habitual short sleep time and habitual sleep loss. Several groups of subjects such as elderly, patients with sleep disorders (i.e. OSAS, insomnia), night-shift workers, new-born babies’ parents [
      • Hirshkowitz M
      • Whiton K
      • Albert SM
      • et al.
      National Sleep Foundation's updated sleep duration recommendations: final report.
      ] have been described to be at higher risk for habitual short sleep.
      Among these groups of people, sleep insufficiency triggers different physiological responses and many negative consequences. As an example, shift work is associated with increased risk for obesity [
      • Di Lorenzo L
      • De Pergola G
      • Zocchetti C
      • et al.
      Effect of shift work on body mass index: results of a study performed in 319 glucose-tolerant men working in a Southern Italian industry.
      ] and metabolic syndrome [
      • Canuto R
      • Garcez AS
      • Olinto MTA
      Metabolic syndrome and shift work: a systematic review.
      ].
      No matter the primary cause, individuals who experiment short sleep may have an increased cardiovascular risk, due to modifications to the autonomic nervous system balance, to the immunological responses and to the hypothalamic-pituitary-adrenal pathways [
      • Tobaldini E
      • Cogliati C
      • Fiorelli EM
      • et al.
      One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians.
      ], and to a higher prevalence of obesity [
      • Cizza G
      • Requena M
      • Galli G
      • de Jonge L
      Chronic sleep deprivation and seasonality: implications for the obesity epidemic.
      ,
      • Marshall NS
      • Glozier N
      • Grunstein RR
      Is sleep duration related to obesity? A critical review of the epidemiological evidence.
      ]. In the following subheading, cardiovascular, inflammatory and hormonal effects induced by short sleep and obesity will be discussed. The bidirectional relationship between obesity and short sleep is summarized in Fig. 1.
      Fig. 1
      Fig. 1The hypothesized model of pathophysiological pathways regarding the bidirectional link between short sleep and obesity. HPA: hypothalamic-pituitary-adrenal axis; T2DM: type 2 diabetes mellitus. RAAS: renin-angiotensin-aldosterone system.

      2.1 Inflammation, autonomic nervous system and vascular response

      Regardless of the cause, acute sleep deprivation (partial sleep restriction to 4 h) is associated with an increase in the production of IL-6, and tumour necrosis factor (TNF), two pro-inflammatory cytokines [
      • Irwin MR
      • Wang M
      • Campomayor CO
      • et al.
      Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation.
      ]. It has been observed that, after a single on-call night shift, young physicians developed a pro-inflammatory state that could be possibly related to an increased sympathetic modulation and vagal withdrawal [
      • Tobaldini E
      • Cogliati C
      • Fiorelli EM
      • et al.
      One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians.
      ]. Sleep disorders and obesity exhibit each a pro-inflammatory status and a sympathetic over-activity, contributing to a potentiated atherosclerotic risk and endothelial dysfunction in sleep-deprived patients with obesity [
      • Tobaldini E
      • Costantino G
      • Solbiati M
      • et al.
      Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases.
      ].
      Moreover, moderate sleep deprivation has been associated with endothelial dysfunction, and inflammatory and endothelial inhibition of endothelium-dependent nitric-oxide-mediated relaxation [
      • Sauvet F
      • Drogou C
      • Bougard C
      • et al.
      Vascular response to 1 week of sleep restriction in healthy subjects. A metabolic response?.
      ]. OSAS has been shown to be an independent causative factor for endothelial dysfunction (e.g., lower nitric oxide levels) that contributes to OSA-related hypertension. On the other hand, patients with obesity show abnormalities of endothelial function such as decreased vasodilation and elevated vasoconstriction responses [
      • Wolk R
      • Shamsuzzaman ASM
      • Somers VK
      Obesity, sleep apnea, and hypertension.
      ]. Since obesity is a main cause of OSAS [
      • Ralls FM
      • Grigg-Damberger M
      Roles of gender, age, race/ethnicity, and residential socioeconomics in obstructive sleep apnea syndromes.
      ,
      • Peppard PE
      • Young T
      • Palta M
      • et al.
      Longitudinal study of moderate weight change and sleep-disordered breathing.
      ,
      • Wing YK
      • Hui SH
      • Pak WM
      • et al.
      A controlled study of sleep related disordered breathing in obese children.
      ], a bidirectional relationship between obesity and sleep disorders is suggested, leading to an additive risk for endothelial dysfunction in population with obesity and OSAS.
      Sleep disturbances are related to an increased renin-angiotensin-aldosterone system stimulation and to aldosterone over-secretion, that may lead hypertension and increased cardiovascular risk [
      • Pecori A
      • Buffolo F
      • Pieroni J
      • et al.
      Primary Aldosteronism and obstructive sleep apnea: casual association or pathophysiological link?.
      ]. For instance, patients with OSAS present higher levels of angiotensin II and aldosterone as compared to their healthy controls matched by body mass [
      • Møller DS
      • Lind P
      • Strunge B
      • Pedersen EB
      Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea.
      ]. Moreover, it was reported that body mass index (BMI) is positivity correlated with plasma aldosterone and angiotensinogen levels [
      • Sharma AM
      • Engeli S
      The renin-angiotensin system in obesity hypertension.
      ]. Once again, a bidirectional relationship seems to exist.
      In summary, obesity itself was associated with an inflammatory imbalance, primary hyper-aldosteronism and a vascular dysfunction, even in not sleep-deprived patients [
      • Magee CA
      • Huang X-F
      • Iverson DC
      • Caputi P
      Examining the pathways linking chronic sleep restriction to obesity.
      ,
      • Pecori A
      • Buffolo F
      • Pieroni J
      • et al.
      Primary Aldosteronism and obstructive sleep apnea: casual association or pathophysiological link?.
      ] Thus, the sympathetic overactivity, the pro-inflammatory status, and the impaired peripheral vasodilatory response induced by a sleep insufficiency could be an additive burden to increase the cardiovascular risk of population with obesity [
      • Tobaldini E
      • Costantino G
      • Solbiati M
      • et al.
      Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases.
      ].

      2.2 Changes in appetite hormones and the complex role of orexin

      Sleep is involved in weight-control pathways, such as insulin secretion, leptin and ghrelin balance, and energy expenditure [
      • Magee CA
      • Huang X-F
      • Iverson DC
      • Caputi P
      Examining the pathways linking chronic sleep restriction to obesity.
      ]. Short sleep duration is associated with low leptin (decreasing satiety) and high ghrelin (increasing hunger) levels, with an effect that is apparently not depending upon several possible confounding factors [
      • Marshall NS
      • Glozier N
      • Grunstein RR
      Is sleep duration related to obesity? A critical review of the epidemiological evidence.
      ].
      Leptin levels are one among the putative mechanisms responsible for hunger and appetite under a sleep-deprived condition, and this hypothesis is consistent with experimental studies in rodents [
      • Mavanji V
      • Billington CJ
      • Kotz CM
      • Teske JA
      Sleep and obesity: a focus on animal models.
      ]. Leptin-deficient mice sleep more than the controlled group, putting leptin in the complex interaction between sleep, energy status, and obesity. Also, increased slow-wave sleep and decreased rapid eye movement sleep was observed following leptin administration in sated animals, but there was no effect of leptin in food-deprived animals [
      • Sinton CM
      • Fitch TE
      • Gershenfeld HK
      The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation.
      ].
      The neuropeptide orexin is another potential hormone involved in the complex interaction between sleep and obesity. Orexin system is involved in many physiological processes such as appetite and sleep-wake cycle. It has been demonstrated that orexin activation promotes wakefulness, feeding and energy metabolism. The loss of orexin-containing neurons in an experimental narcoleptic canine model [
      • Lin L
      • Faraco J
      • Li R
      • et al.
      The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene.
      ], seems to have a causal relationship with non-REM and REM sleep regulatory processes and with the development of narcolepsy [
      • Mavanji V
      • Billington CJ
      • Kotz CM
      • Teske JA
      Sleep and obesity: a focus on animal models.
      ]. The relationship between orexin dysfunction and weight gain is independent from the reduction of food intake [
      • Mavanji V
      • Billington CJ
      • Kotz CM
      • Teske JA
      Sleep and obesity: a focus on animal models.
      ] and increased signalling of orexin receptor-2 prevented obesity and improved leptin sensitivity in mice challenged with a high-fat diet [
      • Funato H
      • Tsai AL
      • Willie JT
      • et al.
      Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity.
      ]. The role of orexin insufficiency on low physical activity as a mediator of poor sleep quality has also been suggested [
      • Blanco-Centurion CA
      • Shiromani PJ
      Beneficial effects of regular exercise on sleep in old F344 rats.
      ]. These findings open potential therapeutic approaches in patients with obesity and sleep insufficiency related to orexin dysfunction [
      • Sinton CM
      • Fitch TE
      • Gershenfeld HK
      The effects of leptin on REM sleep and slow wave delta in rats are reversed by food deprivation.
      ]. In contrast, a recent meta-analysis elicits the hedonic driven as a more plausible explanation for the observed increase in energy intake after partial sleep deprivation. It was suggested a shifted distribution of macronutrient, favouring fat intake at the cost of protein after partial sleep deprivation. Partial sleep deprivation increased total 24-h energy intake and did not affect total 24-h energy expenditure, leading to a positive energy balance of 385 kcal per day. Otherwise, it was speculated that no significant change in energy expenditure is influenced by differences in methods of energy expenditure measurements among studies included in the meta-analysis. Thus, in real-life conditions, partial sleep deprivation may affect a physical activity level that is closely related to reduce energy expenditure [
      • Al Khatib HK
      • Harding S V
      • Darzi J
      • Pot GK
      The effects of partial sleep deprivation on energy balance: a systematic review and meta-analysis.
      ].
      Taken together, all the described neuro-endocrine, metabolic and hedonic changes induced by sleep deprivation seem to lead to a positive energy balance due to at least increased energy intake and reduced energy expenditure, promoting the process that leads to overweight and obesity [
      • Mavanji V
      • Billington CJ
      • Kotz CM
      • Teske JA
      Sleep and obesity: a focus on animal models.
      ,
      • Farooqi IS
      • Jebb SA
      • Langmack G
      • et al.
      Effects of recombinant leptin therapy in a child with congenital leptin deficiency.
      ,
      • Rihm JS
      • Menz MM
      • Schultz H
      • et al.
      Sleep deprivation selectively upregulates an amygdala-hypothalamic circuit involved in food reward.
      ].

      3. Obesity and sleep disorders

      3.1 Obesity and obstructive sleep apnea

      Obstructive Sleep Apnea Syndrome (OSAS) is a sleep syndrome characterized by upper airway recurrent obstruction during sleep. Patients with OSAS report excessive sleepiness, fatigue, and tiredness during the daytime, snoring, abrupt interruption of sleep because of a choking sensation and morning headaches. Together with craniofacial abnormalities, obesity is considered a major risk factor [
      • Jordan AS
      • McSharry DG
      • Malhotra A
      Adult obstructive sleep apnoea.
      ,
      • Young T
      • Skatrud J
      • Peppard PE
      Risk factors for obstructive sleep apnea in adults.
      ,
      • Malhotra A
      • White DP
      Obstructive sleep apnoea.
      ,
      • Shinohara E
      • Kihara S
      • Yamashita S
      • et al.
      Visceral fat accumulation as an important risk factor for obstructive sleep apnoea syndrome in obese subjects.
      ].
      The prevalence of OSAS is almost doubled among male patients with BMI between 25-30 kg/m2 compared to patients with normal BMI (21 vs 11%), and reaches more than 60% of prevalence among subjects with obesity (BMI > 30 kg/m2); a similar trend, with lower prevalence, has also been described for female patients [
      • Ralls FM
      • Grigg-Damberger M
      Roles of gender, age, race/ethnicity, and residential socioeconomics in obstructive sleep apnea syndromes.
      ] while OSA prevalence is estimated to be around 1-6% in children [
      • Peppard PE
      • Young T
      • Palta M
      • et al.
      Longitudinal study of moderate weight change and sleep-disordered breathing.
      ] reaching values up to 60% in children with obesity [
      • Wing YK
      • Hui SH
      • Pak WM
      • et al.
      A controlled study of sleep related disordered breathing in obese children.
      ].
      Populations with obesity are characterized by an increased adiposity around the neck [
      • Schwartz AR
      • Patil SP
      • Laffan AM
      • et al.
      Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches.
      ] that may directly cause a narrowing of the upper respiratory tract [
      • Mayer P
      • Pépin JL
      • Bettega G
      • et al.
      Relationship between body mass index, age and upper airway measurements in snorers and sleep apnoea patients.
      ] thus facilitating hypoxia and apnoea during sleep [
      • Schwartz AR
      • Patil SP
      • Squier S
      • et al.
      Obesity and upper airway control during sleep.
      ]. Fat deposition in the torso may also directly cause a reduction of residual lung capacity and an increase in lung volume that may contribute through traction to collapsing of the pharyngeal airway [
      • Isono S
      Obesity and obstructive sleep apnoea: mechanisms for increased collapsibility of the passive pharyngeal airway.
      ]. Moreover, a complex mechanism involving neuromuscular control of airway patency through leptin, may be involved [
      • Imayama I
      • Prasad B
      Role of leptin in obstructive sleep apnea.
      ]. Current evidence suggests that leptin may have a role in the ventilatory response to hypercapnia, sleep architecture, ventilatory function and upper airway patency [
      • Imayama I
      • Prasad B
      Role of leptin in obstructive sleep apnea.
      ].
      On the other hand, sleep deprivation in patients with OSAS may predispose to weight gain because of increased appetite and reduced physical activity due to excessive sleepiness [
      • Zhu B
      • Shi C
      • Park CG
      • et al.
      Effects of sleep restriction on metabolism-related parameters in healthy adults: a comprehensive review and meta-analysis of randomized controlled trials.
      ]. OSAS has also been described as an independent risk factor for insulin resistance [
      • Ip MSM
      • Lam B
      • Ng MMT
      • et al.
      Obstructive sleep apnea is independently associated with insulin resistance.
      ], systemic inflammation [
      • Ip MSM
      • Lam B
      • Ng MMT
      • et al.
      Obstructive sleep apnea is independently associated with insulin resistance.
      ,
      • Ohga E
      • Tomita T
      • Wada H
      • et al.
      Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1.
      ], and cholesterol metabolism [
      • Ohga E
      • Tomita T
      • Wada H
      • et al.
      Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1.
      ,
      • Börgel J
      • Sanner BM
      • Bittlinsky A
      • et al.
      Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels.
      ].
      Finally both OSA and obesity have been related to increased sympathetic activity, activation of the renin-angiotensin-aldosterone system, endothelial dysfunction and baro-reflex dysfunction [
      • Wolk R
      • Shamsuzzaman ASM
      • Somers VK
      Obesity, sleep apnea, and hypertension.
      ]. All such conditions may contribute to the higher prevalence of hypertension, that may be related to a higher cardiovascular risk observed in patients with obesity and OSAS compared to healthy controls [
      • Wolk R
      • Shamsuzzaman ASM
      • Somers VK
      Obesity, sleep apnea, and hypertension.
      ].
      Several treatment strategies have been proposed for patients with obesity and OSAS. The first step in treating patients with OSA and obesity is assessing patients’ behaviour and encouraging them to achieve weight loss and regular, adequate, physical exercise.
      Behavioural strategies, treatments with orlistat and metformin, used alone or in association, have all shown to be effective in reducing weight in patients with obesity, with the greater weight loss the higher the intensity of the treatment [
      • LeBlanc ES
      • O'Connor E
      • Whitlock EP
      • et al.
      Effectiveness of primary care–relevant treatments for obesity in adults: a systematic evidence review for the U.S. Preventive Services Task Force.
      ]. Current evidence suggests that dietary (low and very low calorie diets) and lifestyle interventions may help patients with obesity and OSAS to reduce weight, are only partially effective in improving OSAS parameters, while clinically they might help to improve symptoms [
      • Araghi MH
      • Chen YF
      • Jagielski A
      • et al.
      Effectiveness of lifestyle interventions on obstructive sleep apnea (OSA): systematic review and meta-analysis.
      ]. Weight loss may also be achieved with more invasive strategies such as bariatric surgery, usually with greater weight loss compared to non-surgical interventions. However, it is not clear whether bariatric surgery has any net benefit in OSA severity compared to non-surgical treatments [
      • Dixon JB
      • Schachter LM
      • O'Brien PE
      • et al.
      Surgical vs conventional therapy for weight loss treatment of obstructive sleep apnea: a randomized controlled trial.
      ].
      Other therapies are directed at preventing upper airway collapse through the application of a positive airway pressure (PAP). As suggested by the American Academy of Sleep Medicine Clinical Practice Guidelines [
      • Patil SP
      • Ayappa IA
      • Caples SM
      • et al.
      Treatment of adult obstructive sleep apnea with positive airway pressure: an American academy of sleep medicine systematic review, meta-analysis, and GRADE assessment.
      ], PAP should be considered as first-line treatment for symptomatic patients with excessive sleepiness (strong recommendation), impaired quality of life due to OSA symptoms or patients with comorbid hypertension (conditional recommendation). Continuous positive airway pressure (CPAP) has shown to have a rapid benefit in sleepiness and quality of life that is greater in patients with higher compliance [
      • Patil SP
      • Ayappa IA
      • Caples SM
      • et al.
      Treatment of adult obstructive sleep apnea with positive airway pressure: an American academy of sleep medicine systematic review, meta-analysis, and GRADE assessment.
      ,
      • Tomfohr LM
      • Ancoli-Israel S
      • Loredo JS
      • Dimsdale JE
      Effects of continuous positive airway pressure on fatigue and sleepiness in patients with obstructive sleep apnea: data from a randomized controlled trial.
      ]. Nevertheless, is still controversial whether CPAP treatment in patients with OSAS might have any net benefit on cardiovascular risk and overall mortality [
      • Patil SP
      • Ayappa IA
      • Caples SM
      • et al.
      Treatment of adult obstructive sleep apnea with positive airway pressure: an American academy of sleep medicine systematic review, meta-analysis, and GRADE assessment.
      ].

      3.2 Obesity and insomnia

      Insomnia is a relevant problem in industrialized countries with a prevalence in Europe ranging from 5.7% to 19% [
      • Riemann D
      • Baglioni C
      • Bassetti C
      • et al.
      European guideline for the diagnosis and treatment of insomnia.
      ]. According to the ICSD3, insomnia is defined as a disturbance of sleep onset or sleep maintenance, or poor sleep quality; sleep disturbances should occur at least 3 times a week over a period of 3 months and must be accompanied by daytime symptoms such as fatigue/malaise, memory impairment or irritability. No quantitative criteria in terms of sleep duration, sleep-onset latency, or duration of nocturnal awakenings are required to make a diagnosis [
      • Riemann D
      • Baglioni C
      • Bassetti C
      • et al.
      European guideline for the diagnosis and treatment of insomnia.
      ].
      Most of the available literature evaluates the correlation between obesity and short sleep duration, which, according to the definition, is not synonymous of insomnia. Indeed, several cross-sectional studies have shown a correlation between short sleep and increased risk of obesity both in children and in adults [
      • Cappuccio FP
      • Taggart FM
      • Kandala N-B
      • et al.
      Meta-analysis of short sleep duration and obesity in children and adults.
      ]. A meta-analysis of longitudinal studies seems to confirm the association between short sleep and risk of future obesity [
      • Wu Y
      • Zhai L
      • Zhang D
      Sleep duration and obesity among adults: a meta-analysis of prospective studies.
      ]. However, conclusive results are still lacking.
      Interestingly, the analysis of longitudinal data, although limited, showed that having obesity did not increase the risk of future insomnia compared to normal-weight subjects, while the evidence for the association between insomnia and future obesity is inconclusive [
      • Chan WS
      • Levsen MP
      • McCrae CS
      A meta-analysis of associations between obesity and insomnia diagnosis and symptoms.
      ,
      • Singareddy R
      • Vgontzas AN
      • Fernandez-Mendoza J
      • et al.
      Risk factors for incident chronic insomnia: a general population prospective study.
      ].
      Making it more complicated, all cited studies must be interpreted taking into account the presence of several confounding factors such as social conditions, demographics, and comorbidities.
      Considering all these limitations, the association between insomnia and obesity seems to be stronger in young compared to older adults but a robust association is far from being demonstrated, and conclusions regarding the potential role of insomnia in determining obesity, or conversely on the causative role of obesity on insomnia, must be considered speculative. Indeed, so far few studies evaluated the role of sleep extension in dietary intake and appetite with evidence of reduced free sugar intakes and reduced overall appetite and desire for sweet and salty foods; no difference in terms of BMI, body weight, body fat, and increased physical activity was demonstrated [
      • Henst RHP
      • Pienaar PR
      • Roden LC
      • DE Rae
      The effects of sleep extension on cardiometabolic risk factors: a systematic review.
      ].
      In conclusion, considering the presence of several inconclusive data, we can state that the evidence of a strong link between insomnia and obesity warrant future investigations.

      3.3 Obesity and restless-leg syndrome

      Restless-leg-syndrome (RLS) has a prevalence of around 10% in the adult general population, increasing with age [
      • Phillips B
      • Hening W
      • Britz P
      • Mannino D
      Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll.
      ]. It is characterized by an urge to move the legs accompanied or caused by an uncomfortable and unpleasant sensation in the legs begin or worsen during period of resting or inactivity and partially or totally relieved by movement such as walking or stretching [
      • Allen RP
      • Picchietti DL
      • Garcia-Borreguero D
      • et al.
      Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance.
      ].
      Several studies have shown a higher risk of RLS in adults and adolescents with obesity that persists even when several confounding factors are taken into account [
      • Baran RT
      • Atar M
      • Pirgon Ö
      • et al.
      Restless legs syndrome and poor sleep quality in obese children and adolescents.
      ,
      • Lin S
      • Zhang H
      • Gao T
      • et al.
      The association between obesity and restless legs syndrome: a systemic review and meta-analysis of observational studies.
      ]. Also, higher levels of cholesterol seem to increase the risk of developing RLS [
      • De Vito K
      • Li Y
      • Batool-Anwar S
      • et al.
      Prospective study of obesity, hypertension, high cholesterol, and risk of restless legs syndrome.
      ]. A key role of dopaminergic hypofunction in the central nervous system (CNS) has been hypothesized considering the positive therapeutic response to dopaminergic drugs [
      • Allen RP
      • Picchietti D
      • Hening WA
      • et al.
      Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.
      ]. Population with obesity have decreased dopamine D2 receptor availability in the brain [
      • Wang GJ
      • Volkow ND
      • Logan J
      • et al.
      Brain dopamine and obesity.
      ], thus dopaminergic hypofunction could be a common causal origin in obesity and RLS. In this complex pathophysiological pathway, deficiencies of iron, a cofactor in dopamine production, seems to have an important role as well, although iron metabolism has not been consistently associated with RLS [
      • Innes KE
      • Selfe TK
      • Agarwal P
      Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review.
      ].
      Supporting the correlation between obesity and RLS, a study by Ozdas et al. has demonstrated that weight loss obtained with bariatric surgery lead to an improvement of RLS symptoms, with around 86% of patients that discontinued medications after 12 months from bariatric surgery [
      • Ozdas S
      • Oner RI
      Influence of obesity surgery on restless leg syndrome.
      ].
      Another aspect is the frequent coexistence of RLS and OSAS. It is reasonable to hypothesize that, being obesity more commonly also in patients with OSA, a considerable group of patients could suffer from both diseases, OSAS and RLS. However, there is no consensus on the prevalence of OSAS in patients with RLS [
      • Lin S-W
      • Chen Y-L
      • Kao K-C
      • et al.
      Diseases in patients coming to a sleep center with symptoms related to restless legs syndrome.
      ,
      • Winkelman JW
      • Redline S
      • Baldwin CM
      • et al.
      Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study.
      ]. Bianchi et al., have shown that among patients with RLS symptoms and no OSAS symptoms, the proportion of patients with elevated apnea-hypopnea index was more than 30%, suggesting the presence of occult OSAS in patients with RLS [
      • Bianchi MT
      • Goparaju B
      • Moro M
      Sleep apnea in patients reporting insomnia or restless legs symptoms.
      ]. It is therefore important to consider the co-presence of these two diseases, also because treatment of OSAS has been shown to improve RLS symptoms, leading to a reduction in drug therapy in more than half of the patients [
      • Silva C
      • Peralta AR
      • Bentes C
      The urge to move and breathe - the impact of obstructive sleep apnea syndrome treatment in patients with previously diagnosed, clinically significant restless legs syndrome.
      ].
      In conclusion, RLS is associated with several cardiovascular risk factors, such as physical inactivity, high serum cholesterol, diabetes, and obesity; moreover, RLS determines a reduction in sleep quality and quantity which itself has been demonstrated to be a cardiovascular risk factor. Therefore, is of pivotal importance to reduce modifiable risk factor such as obesity to reduce the presence of other conditions that could increase the global cardiovascular risk. More prospective studies evaluating the role of treating obesity in ameliorating RLS symptoms are necessary.

      3.4 Obesity and periodic limb movement disorder

      Periodic Limb Movement during sleep (PMLS) is a condition characterized by involuntary movements of the limbs, usually the inferior limbs, during NREM sleep. PMLS is more common over 65 years old but can develop at any age. Many individuals can be asymptomatic, making the diagnosis more difficult. However, if PMLS are >15/h in adults and determine sleep disturbance or other functional impairment such as irritability or mood changes a diagnosis of Periodic Limb Movement Disorder (PMLD) can be made [
      • Sateia MJ
      International classification of sleep disorders-third edition highlights and modifications.
      ]. PMLS are often associated with other sleep disorder such as RLS, OSAS and narcolepsy and diagnosis of isolated PMLD is considered to be rare, thus literature related purely to PMLD is very scanty and there is insufficient evidence to give recommendation on pharmacologic therapies in isolated PLMD [
      • Aurora RN
      • Kristo DA
      • Bista SR
      • et al.
      The treatment of restless legs syndrome and periodic limb movement disorder in adults–an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline.
      ]. While there are some data on the association between PMLD and being a shift worker, snoring, daily coffee intake and use of hypnotics and stress [
      • Ohayon MM
      • Roth T
      Prevalence of restless legs syndrome and periodic limb movement disorder in the general population.
      ], no association between PMLD and obesity or metabolic syndrome has been described. There are some contrasting results on a positive association between PMLS and BMI [
      • Szentkirályi A
      • Stefani A
      • Hackner H
      • et al.
      Prevalence and associated risk factors of periodic limb movement in sleep in two German population-based studies.
      ]; however, as already mentioned, PMLS can be present in several sleep disorder, thus a strict causal relationship is hard to be determined.

      3.5 Obesity and shift work

      In the past few decades the number of shift workers has extremely increased, with 21% of all workers in Europe reporting working shifts in 2016 [

      Publications Office of the European Union (2017) Sixth European Working Conditions Survey – Overview report (2017 update). Luxembourg.

      ].
      Shift work-sleep disorder is a condition that affects people who, for job reasons, work outside the normal day-time working schedule (7-8 a.m. until 5-7 p.m.). Shift work sleep disorder is categorized as a circadian rhythm sleep-wake disorder, a class of sleep disorders characterized by a misalignment between the endogenous circadian rhythm and the sleep-wake schedule desired causing the presence of a sleep-wake disturbance (ie, insomnia or excessive sleepiness) determining distress or impairment [
      • Sateia MJ
      International classification of sleep disorders-third edition highlights and modifications.
      ].
      Several studies have demonstrated that shift workers suffer more frequently of overweight, obesity and metabolic syndrome compared to workers with a normal working schedule [
      • Brum MCB
      • Dantas Filho FF
      • Schnorr CC
      • et al.
      Night shift work, short sleep and obesity.
      ,
      • Pietroiusti A
      • Neri A
      • Somma G
      • et al.
      Incidence of metabolic syndrome among night-shift healthcare workers.
      ]. This association has been confirmed also by a recent meta-analysis by Liu et al., that found that shift workers might have an increased risk of overweight and obesity of 25% and 17%, respectively [
      • Liu Q
      • Shi J
      • Duan P
      • et al.
      Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis.
      ]. A meta-analysis conducted only on shift work nurses found that there was a slight increase in the risk of obesity (12% increased risk) only in the subgroup of night shift workers [
      • Zhang Q
      • Chair SY
      • Lo SHS
      • et al.
      Association between shift work and obesity among nurses: A systematic review and meta-analysis.
      ].
      For obvious reasons, night shift workers are more exposed to irregular sleep-wake cycle, shorter sleep and circadian misalignment compared to day shift workers and subjects with a normal working schedule. Consequently, they are both more predisposed to develop the pathophysiological alterations of glucose metabolism, lipid homeostasis and appetite regulation that we have already described, and more prone to over-eating a poor-nutrient diet based on a more extensive consumption of snacks and soft drinks [
      • O'Brien VM
      • Nea FM
      • Pourshahidi LK
      • et al.
      Overweight and obesity in shift workers: associated dietary and lifestyle factors.
      ] and to have reduced physical activity due to day-time sleepiness.
      Moreover, it has been found that night shift workers with overweight and obesity were also less motivated for behavioural change in lifestyle, in particular those with long working hours [
      • Tanikawa Y
      • Kimachi M
      • Ishikawa M
      • et al.
      Association between work schedules and motivation for lifestyle change in workers with overweight or obesity: a cross-sectional study in Japan.
      ]. Morgan et al. evaluated the benefit of a workplace-based weight loss program that targeted overweight and obese male shift workers, based on an information session covering education about energy balance, the challenges of shift work relating to diet and physical activity, weight loss tips, and behaviour change strategies (i.e. self-monitoring, goal setting and social support). Subjects enrolled were also provided with a weight loss handbook and could have individualized feed-back and support by research team after providing information on daily eating and exercise diaries on a weight loss website. The authors found that the workplace-based weight loss program had benefit not only on weight loss (-4.3 Kg compared to control group at 14- week follow-up) but also on waist circumference, BMI, systolic blood pressure, resting heart rate and increased physical activity [
      • Morgan PJ
      • Collins CE
      • Plotnikoff RC
      • et al.
      Efficacy of a workplace-based weight loss program for overweight male shift workers: the Workplace POWER (Preventing Obesity Without Eating like a Rabbit) randomized controlled trial.
      ].
      Considering that shift works are now integrated in our society and that they are fundamental to guarantee several activities, shift workers (night shift workers in particular) should be targeted with lifestyle and dietary interventions to help protect against overweight, obesity and associated comorbidities. Available literature suggests that using a workplace-based weight loss program could be a valid option [
      • Morgan PJ
      • Collins CE
      • Plotnikoff RC
      • et al.
      Efficacy of a workplace-based weight loss program for overweight male shift workers: the Workplace POWER (Preventing Obesity Without Eating like a Rabbit) randomized controlled trial.
      ].

      4. Summary

      Summarizing the current knowledge, sleep deprivation increases sympathetic activity discharge and pro-inflammatory cytokines release, inducing an endothelial dysfunction [
      • Irwin MR
      • Wang M
      • Campomayor CO
      • et al.
      Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation.
      ,
      • Tobaldini E
      • Cogliati C
      • Fiorelli EM
      • et al.
      One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians.
      ,
      • Tobaldini E
      • Costantino G
      • Solbiati M
      • et al.
      Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases.
      ,
      • Sauvet F
      • Drogou C
      • Bougard C
      • et al.
      Vascular response to 1 week of sleep restriction in healthy subjects. A metabolic response?.
      ]. Moreover, sleep deprivation causes an intake and energy expenditure imbalance due to its effect in hormonal responses, namely a reduction in orexin and leptin and an increment in ghrelin [
      • Mavanji V
      • Billington CJ
      • Kotz CM
      • Teske JA
      Sleep and obesity: a focus on animal models.
      ]. These appetite regulation alterations , associated with an upregulation of food valuation, independent of hormonal changes [
      • Lubkin M
      • Stricker-Krongrad A
      Independent feeding and metabolic actions of orexins in mice.
      ], and the reduction in physical activity, likely due to the sense of fatigue and sleepiness in the active phase, all play a role in causing the short circuit between sleep deprivation and overweight [
      • Magee CA
      • Huang X-F
      • Iverson DC
      • Caputi P
      Examining the pathways linking chronic sleep restriction to obesity.
      ].
      Thus, sleep deprivation could increase the risk of obesity and metabolic syndrome, independently from the presence of an established sleep disorder [
      • Magee CA
      • Huang X-F
      • Iverson DC
      • Caputi P
      Examining the pathways linking chronic sleep restriction to obesity.
      ,
      • Marshall NS
      • Glozier N
      • Grunstein RR
      Is sleep duration related to obesity? A critical review of the epidemiological evidence.
      ]. Otherwise, the bidirectional relationship between obesity and sleep disorders should also be considered in the opposite direction.
      Data on the regulation among obesity and the most common sleep disorders (i.e. OSAS, RLS, PMLS, nigh shift) suggest a close bi-directional causal-effect relation between sleep disorders and obesity. In such a vicious circle, it is hard to establish what comes first. Despite the debate about what comes first (sleep disorders or obesity), it is well-established that sleep deprivation is a new modifiable risk factor [
      • Montano N
      • Fiorelli E
      • Tobaldini E
      Sleep duration and the heart: I sleep, therefore I beat.
      ] for cardiometabolic disorders, as well as that population with obesity have a great prevalence of sleep disorders that interact with a complex network of behaviour and physiological aspects. In conclusion, being these two conditions so intermingled and sharing relevant pathophysiological pathways for cardiometabolic risk, we would like to support the good clinical practice to always assess the sleep status and investigating for possible sleep disorders when dealing with people living with obesity.

      Declaration of competing interest

      All the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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