This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Mood disorders: A potential link between ghrelin and leptin on human body?
Stalo Zarouna, Greta Wozniak, Anastasia Ioannis Papachristou
Stalo Zarouna, Psychology Department, University of Cyprus, Nicosia 1678, Cyprus
Greta Wozniak, Basic Medical Science, Medical Pharmacology, Medical School, University of Cyprus, Nicosia 1678, Cyprus
Anastasia Ioannis Papachristou, School of Medicine, University of Crete, Voutes Campus, Heraklion, GR-71003 Crete, Greece
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed to this paper.
Conflict-of-interest: None conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Greta Wozniak, MD, PhD, Assistant Professor of Basic Medical Science, Medical Pharmacology, Medical School, University of Cyprus, Kallipoleos 75, Nicosia 1678, Cyprus. email@example.com
Telephone: +357-22-895221 Fax: +357-22-895221
Received: September 26, 2014 Peer-review started: September 28, 2014 First decision: December 17, 2014 Revised: January 9, 2015 Accepted: January 30, 2015 Article in press: February 2, 2015 Published online: May 20, 2015
Leptin and ghrelin are two hormones associated with multiple physiological functions, especially energy balance. Leptin is an adipocyte-secreted hormone discovered in 1950 and ghrelin which was found in 1999, is a peptide hormone produced and secreted in the stomach. A number of previous studies showed that these hormones could be associated with different types of mood disorders. The results of previous studies, nevertheless, are confounded by diverse sample selection and different methodologies. A search for related articles in the PubMed database was attempted. The search covered studies, reports, reviews and editorials published in the last ten years. Older references served as auxiliary sources for comparison purposes. However, due to the different results of the studies, there is a need for more investigation in order to establish the exact biochemical mechanisms that are responsible for these diseases and ghrelin’s and leptin’s effects on mood.
Core tip: Mood disorders are affecting a major amount of the world population. Considering the multiple factors that are contributing in the development of mood disorders, this review emphasizes on the role of leptin and ghrelin hormones. These two hormones have a key role in energy balance but they also have an effect on other physiological functions too, therefore we emphasize on the recent findings which raise a potential link between the hormones and the disorders of mood.
Citation: Zarouna S, Wozniak G, Papachristou AI. Mood disorders: A potential link between ghrelin and leptin on human body? World J Exp Med 2015; 5(2): 103-109
Mood disorders (MD) cover a wide range of mental illnesses and many studies have examined different aspects of them, such as their effect on social life of a person and how they are evolutionary changing through the years. Anxiety disorders and major depressive disorder (MDD) are the most prevalent mental disabilities and affect a large amount of the world population. The etiology of MDs is diverse. Genetic factors like family history, as well as psychological and socioeconomic features have a key role on the development of MDs[2-4]. As far as genetic factors are concerned, there has been a great deal of research on a specific gene called brain-derived neurotrophic factor (BDNF), which has an important role to the pathophysiology of MDs but which might also contribute to the therapeutic mechanisms, by exerting antidepressant effects[5,6]. BDNF is involved in neuronal plasticity, and has antidepressant effects probably due to its interaction with serotonin systems[7,8]. This interaction monitors the development and plasticity of the neural circuits which have a role in MDs. Likewise, antidepressant drugs can alter the levels of neurotrophic factors and therefore are able to contribute in neuronal plasticity.
Different parts of the brain are involved in the regulation of mood and the expression of emotions, as well as other functions, like reward processing. Neuroimaging and neuropathological studies support that the medial prefrontal cortex, the caudolateral orbital cortex, the amygdala, the hippocampus and the ventromedial parts of the basal ganglia are networks which modulate emotional behavior. There is evidence that the function of these structures is altered in patients with MDs[11-13]. For example, in cases of stress and long-term depression, the hippocampus and the prefrontal cortex are subjected to atrophy while amygdala is subjected to hyperaction. Another important site of the brain that associates with MDs is the hypothalamic-pituitary-adrenal axis (HPA) which consists of the hypothalamus, the pituitary and adrenal cortex. The regulation of the HPA-axis depends on the inputs that the paraventricular nucleus receives but it is also auto-regulatory. The auto-regulation is important for allostasis and it is hypothesized that allostatic change may link to MDs. Moreover, a dysregulation of the HPA axis it is often connected with MDD.
The areas of the brain mentioned above are not only associated to MDs but they also have an important role in feeding behavior and nutrition hormones. Whether food choice and mood have a negative or a positive relationship depends on the psychological and the neurohormonal characteristics of a person. The correlation of MDs and food intake is supported by the irregularities of the HPA axis function. Danaei et al reported that obesity has become a pandemic in the last five decades. Numerous studies have showed that obesity and MDs are related. More specifically, depression and major depression are reported as risks factors for developing obesity particularly for women[19-25].
There is evidence that obesity may be a risk factor for anxiety disorders too[26,27]. Under normal conditions, the brain is activated to confront perceived threats, by altering the HPA axis and by entering into an anabolic state. When an individual faces chronic stress, however, the metabolism shifts to catabolic state.
HPA axis is not the only region of the brain that is affected by MDs. The cortex, the limbic system, the midbrain and the brainstem are also subjected to changes. When the physiological pathways are activated due to chronic stress, cortisol rises, and appetite hormones as well as weight are altered. The reinforced motivation for food is caused by the increased secretion of glucocorticoids and which in turn leads to obesity.
Another hypothesis which supports the relation between obesity and MDs refers to the inefficiency of leptin signaling. Leptin is a 16-kDa protein which is encoded by the obese (ob) gene and is mainly secreted by the white adipose tissue. Leptin suppresses food intake, whereas another hormone called ghrelin stimulates appetite. Ghrelin, is a hormone secreted from stomach but it can be found in small amounts in the brain too. Surprisingly, obese individuals have high circulating leptin levels, in contrast to the orexigenic hormone which is found in low levels. This suggests that obese people are leptin-resistant.
In this review, we focus on recent findings regarding the role of ghrelin and leptin in the regulation of MDs such MDD, and we refer to the mechanism of the pathophysiology of MD. This review points at the potential link between ghrelin and leptin on human body and MDs, as they serve as complementary hormones with multiple functions. This review takes into account information from 2004 to 2014 on the leptin and ghrelin hormones and more specifically, their function in the central nervous system (CNS), and their potential role in MDs.
LEPTIN’S ROLE IN MOOD REGULATION
Leptin has a key role in energy intake and expenditure. Specifically, circulating leptin sends information to the hypothalamus about the changes of energy intake and how much energy is stored in the adipose tissue. Leptin is produced peripherally in the adipose tissue so it is essential to cross the blood-brain barrier to act inside the brain. It is believed that the transportation of leptin into the brain follows a saturable system and crosses the blood-brain barrier via LepRs which are located in nonneural cells in the meninges, choroid and blood vessels[38,39]. The transportation of leptin becomes more intensive in the hypothalamic ARC (Arcuate Nucleus), a major site for leptin signaling and resistance. Leptin affects two types of neurons in the ARC; a group of neurons secrets the protein POMC (proopiomelanocortin) together with cocaine and amphetamine-regulated transcript (CART), whereas the other class of neurons expresses neuropeptide Y (NPY) and AgRP (agouti-related protein). The NPY and AgRP peptides are expressed with the reduction of leptin, while CART and POMC are suppressed.
The HPA is a brain area that was systematically found to be associated with MDs. In depression, the overstimulation of HPA axis caused by glucocorticoid receptor resistance increase leptin synthesis and secretion. Thus, studies on mouse models showed that leptin might modulate HPA function. Specifically, it seems that peripheral and hippocampal administration of leptin mitigates symptoms of depression[33,43,44]. The results of some human studies are consistent with animal studies as they showed that leptin reduces symptoms of depression and had anxiolytic effects. There is a study by Jimenez et al, however, which suggests that leptin might predict post-stroke depression, as higher leptin levels were found in patients with depression after stroke. Similarly, a cross-sectional study by Pasco et al, demonstrated that depressive disorders can be predicted by high serum leptin levels among female non-smokers. In addition, elevated leptin levels as well as visceral fat seem to predict depressive symptoms in old men. Likewise, in a longitudinal study by Milaneschi et al high levels of leptin and abdominal adiposity were a high risk factor for the development of depressed mood over a 9-year follow up.
Studies in humans have given controversial evidence about the role of leptin in MDs. A few studies reported that depression is associated with low leptin levels independent of body mass[45,50]. Furthermore, one study revealed that female suicide attempters with MDD had lower cerebrospinal fluid leptin than in the group with other disorders, even though both groups had similar body mass index (BMI). Patients with MDD, Obsessive Compulsive Disorder (OCD) and comorbid depression were examined in various studies. It was found that these patients had significantly lower leptin levels and higher cortisol levels than healthy controls and patients without comorbid depression and MDD. Furthermore, Emul et al found that the comorbid MDD with OCD group did not have any difference compared to patients with pure OCD and controls.
On the contrary, other studies showed that patients with different types or symptoms of depression, such as atypical depressive disorders, depressed mood and sleep disturbances as well as social isolation, had higher leptin levels than a control group[47,54-56]. Researchers who investigated the effects of leptin on antidepressant treatments found out that leptin was increased during drug treatment[42,57]. As far as anxiety is concerned, Lawson et al found that increased symptoms of anxiety were related with low levels of leptin, independent of BMI and weight, supporting that leptin is an anti-stress hormone (Table 1).
Table 1 Leptin in patients with mood disorders according study’s since 2004.
Ghrelin is a 28-amino acid peptide, secreted from stomach and functions as an orexigenic hormone, while it is increased before meals and reduced after meals[58-61]. Ghrelin is acylated [acyl ghrelin (AG)] by ghrelin O-acyl transferase in the stomach and 10%-20% of circulating ghrelin exists in this form. Acylation is required for ghrelin to activate its receptor, the growth hormone secretagogue receptor (GHSR). In particular, it promotes food intake and adiposity sending a peripheral signal to the hypothalamus through the neuropeptide Y and agouti-related protein. Even though AG has a major role in energy balance it also contributes in other biological functions too, such as the regulation of insulin secretion, the regulation of glucose metabolism and influences the pituitary-gonadal axis.
Although ghrelin is present in the stomach and other peripheral tissues like the pancreas, it is also found in smalls amounts in the hypothalamus[34,59,63]. Therefore ghrelin affects the CNS and does not act only as a hunger signal. There is evidence that plasma ghrelin passes the blood-brain barrier and binds with the hippocampus thus promoting synaptic plasticity. AG activates GHSR-expressing neurons of the hypothalamus to stimulate food intake and secretion of growth hormone (GH). Ghrelin acts through the GHSR thus it stimulates the secretion of the GH from the anterior lobe of pituitary[60,66,67]. As an orexigenic hormone, ghrelin has an important role in weight gain and adiposity. Druce et al though, found that obese people do not have different ghrelin levels that lean individuals. The studies that focused on the extremes of the BMI range, found that the correlation between ghrelin levels and BMI are inversed; the lower the BMI the higher are the ghrelin levels. On the contrary, leptin and ghrelin are correlated positively.
As it was mentioned already, ghrelin does not only act as a hunger signal but it is also involved in reward, motivation and signaling pathways, and is in this way linked with stress, anxiety disorders and depression. Carlini et al suggest that the relation between the limbic areas and the hypothalamus create a circuit that connects emotional states and eating behavior. Moreover, Nakashima et al, found an association between a gene polymorphism and depression. Different studies in animals yielded contrasting findings. Some showed that ghrelin could be an anxiogenic hormone whereas others revealed that it can have anxiolytic and anti-depressive responses[70,72-76]. High levels of ghrelin were observed after conditions of energy insufficiency but also after acute or chronic stress.
In human studies too contrasting findings were reported. Some researches did not find any differences in ghrelin levels between patients with major depression and controls[62,78,79] while other researchers suggested that plasma ghrelin levels as well as pre-proghrelin mRNA levels are elevated in conditions of stress[77,80]. Ozsoy et al, for example, found higher levels in serum ghrelin levels in depressive patients, than in controls and they also found that high serum ghrelin levels were normalized by treatment. An improvement of depressive symptoms was found in men with MDD after they were administrated with ghrelin. On the other hand, a reduction of ghrelin levels in MDD patients revealed a reduction of psychopathological symptoms[83,84]. Barim et al examined patients with depression before and after treatment with citalopram and showed that the levels of ghrelin of the depression patients were lower than the ones of healthy individuals in both periods of time. This antidepressant effect of high levels of ghrelin might be associated with the restriction of food or with hyperactivity of the HPA axis in depression and anxiety which increases the stimulation of ACTH and glucocorticoids that increase ghrelin levels[76,82-86]. The change in ghrelin levels may imply a reaction to symptoms of depression, such as loss of weight and appetite (Table 2).
Table 2 Ghrelin in patients with mood disorders according study’s since 2007.
Leptin and ghrelin are two complementary hormones that have a major impact on energy balance. Leptin restrains gastric ghrelin to secret and inhibits the stimulation of feeding. It is hypothesized that these hormones control energy homeostasis through two independent systems. Leptin functions as a feedback mechanism that signals to key regulatory centers in the brain to inhibit food intake and to regulate body weight and energy homeostasis. Ghrelin stimulates the activity of neurons expressing NPY, AgRP and orexin. Furthermore, ghrelin has an inhibitory effect on POMC neurons and CRH-producing neurons. Even though leptin as well as ghrelin, exert peripheral signals, evidence from studies in animals showed that leptin is also produced in the brain and that ghrelin is synthesized in neuronal cells of the hypothalamus[88,89]. Due to their multiple functions, researchers are trying to discover their effect on MDs. Many studies showed that the mechanisms that underlie their function are critical to the development and the treatment of MDs.
Studies with patients with depression seem to suggest that that the two hormones might exert antidepressant effects, due to the change of their levels in patients with depression as opposed to controls. However, the potential antidepressant effect of the hormones is not clear, as other studies did not find any changes to serum levels between patients with depression and control and some other studies even report reverse results. Particularly, some studies revealed that high levels of the hormones are associated with depression and anxiety disorders, while others showed that depressive patients have low levels of the hormones, even before and after treatment, compared to controls. It is clear however, that the neural circuits involved in the regulation of food intake via ghrelin and leptin, affect emotional changes too. The systems in the CNS that are involved in energy balance are associated with the regulation of emotions. The ARC of the hypothalamus and the HPA axis are two critical areas both in MDs and for the secretion and synthesis of ghrelin and leptin.
Chronic stress can lead to changes in eating patterns and metabolism, and eating and metabolism may in turn affect mood. This is only a conjecture for now as it has not been thoroughly studied to date. The researchers concluded that they had identified a previously unknown role for ghrelin in regulating mood. Results of studies have shown that ghrelin levels can be increased by chronic stress and can reduce anxiety and depression-like behaviours. These findings may be relevant to conditions such as anorexia, where ghrelin levels are known increased. Much more research will be needed to look into whether this hormone plays a role in anxiety and depression in humans.
The current review indicates that leptin and ghrelin are indeed involved in the process of MDs. The variety of methodologies used in different studies over the past 10 years might be responsible for the conflicting findings. It appears that the mechanism in which these two hormones affect mood or are affected by mood could be further enlightened if a study is repeated controlling for dual diagnosis and comorbidity, as well as the severity of depression. Focusing on MDD can be a better indicator of biological markers since melancholia can be a result of every day events. Therefore, findings for MDD can be used as a precursor for examining other MDs with closely related symptoms.
Leptin and ghrelin do not only have a key role in energy homeostasis but they have also pleiotropic effects on the CNS and periphery. The evidence from different studies on the association between MDs and the two hormones is controversial. This can be explained by the diverse characteristics of the patients participating in the studies, the various methodologies that are used and the different measurements of the levels of hormones. As a result, the role of ghrelin and leptin in MDs is not yet clearly established. It will be interesting to examine more extensively the role of the two hormones in all of the different types of MDs in order to reveal potential common features of emotional changes and changes of the hormones levels.
P- Reviewer: Masaki T, Unger M S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ
Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States.Annu Rev Public Health. 2008;29:115-129.
Merikangas KR, Low NC. The epidemiology of mood disorders.Curr Psychiatry Rep. 2004;6:411-421.
Kalia M. Neurobiological basis of depression: an update.Metabolism. 2005;54:24-27.
Belmaker RH, Agam G. Major depressive disorder.N Engl J Med. 2008;358:55-68.
Hashimoto K, Shimizu E, Iyo M. Critical role of brain-derived neurotrophic factor in mood disorders.Brain Res Brain Res Rev. 2004;45:104-114.
Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions.Psychiatry Clin Neurosci. 2010;64:341-357.
Craddock N, Forty L. Genetics of affective (mood) disorders.Eur J Hum Genet. 2006;14:660-668.
Martinowich K, Lu B. Interaction between BDNF and serotonin: role in mood disorders.Neuropsychopharmacology. 2008;33:73-83.
Calabrese F, Molteni R, Racagni G, Riva MA. Neuronal plasticity: a link between stress and mood disorders.Psychoneuroendocrinology. 2009;34 Suppl 1:S208-S216.
Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression.Brain Struct Funct. 2008;213:93-118.
Kanner AM. Is major depression a neurologic disorder with psychiatric symptoms?Epilepsy Behav. 2004;5:636-644.
Haldane M, Frangou S. New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings.Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:943-960.
Brambilla P, Glahn DC, Balestrieri M, Soares JC. Magnetic resonance findings in bipolar disorder.Psychiatr Clin North Am. 2005;28:443-467.
McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain.Metabolism. 2005;54:20-23.
Watson S, Mackin P. HPA axis function in mood disorders.Psychiatry. 2006;5:166-170.
Gibson EL. Emotional influences on food choice: sensory, physiological and psychological pathways.Physiol Behav. 2006;89:53-61.
Soczynska JK, Kennedy SH, Woldeyohannes HO, Liauw SS, Alsuwaidan M, Yim CY, McIntyre RS. Mood disorders and obesity: understanding inflammation as a pathophysiological nexus.Neuromolecular Med. 2011;13:93-116.
Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ, Ezzati M. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors.PLoS Med. 2009;6:e1000058.
Maniam J, Morris MJ. The link between stress and feeding behaviour.Neuropharmacology. 2012;63:97-110.
McIntyre RS, Konarski JZ, Wilkins K, Soczynska JK, Kennedy SH. Obesity in bipolar disorder and major depressive disorder: results from a national community health survey on mental health and well-being.Can J Psychiatry. 2006;51:274-280.
Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, Kessler RC. Association between obesity and psychiatric disorders in the US adult population.Arch Gen Psychiatry. 2006;63:824-830.
Mather AA, Cox BJ, Enns MW, Sareen J. Associations of obesity with psychiatric disorders and suicidal behaviors in a nationally representative sample.J Psychosom Res. 2009;66:277-285.
de Wit L, Luppino F, van Straten A, Penninx B, Zitman F, Cuijpers P. Depression and obesity: a meta-analysis of community-based studies.Psychiatry Res. 2010;178:230-235.
Atlantis E, Baker M. Obesity effects on depression: systematic review of epidemiological studies.Int J Obes (Lond). 2008;32:881-891.
McElroy SL, Kotwal R, Malhotra S, Nelson EB, Keck PE, Nemeroff CB. Are mood disorders and obesity related? A review for the mental health professional.J Clin Psychiatry. 2004;65:634-651, quiz 730.
Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis.Int J Obes (Lond). 2010;34:407-419.
Bazhan N, Zelena D. Food-intake regulation during stress by the hypothalamo-pituitary-adrenal axis.Brain Res Bull. 2013;95:46-53.
Jauch-Chara K, Oltmanns KM. Obesity--a neuropsychological disease? Systematic review and neuropsychological model.Prog Neurobiol. 2014;114:84-101.
Dallman MF, Pecoraro NC, La Fleur SE, Warne JP, Ginsberg AB, Akana SF, Laugero KC, Houshyar H, Strack AM, Bhatnagar S. Glucocorticoids, chronic stress, and obesity.Prog Brain Res. 2006;153:75-105.
Vicennati V, Pasqui F, Cavazza C, Pagotto U, Pasquali R. Stress-related development of obesity and cortisol in women.Obesity (Silver Spring). 2009;17:1678-1683.
Dallman MF. Stress-induced obesity and the emotional nervous system.Trends Endocrinol Metab. 2010;21:159-165.
Taylor V, MacQueen G. Associations between bipolar disorder and metabolic syndrome: A review.J Clin Psychiatry. 2006;67:1034-1041.
Lu XY. The leptin hypothesis of depression: a potential link between mood disorders and obesity?Curr Opin Pharmacol. 2007;7:648-652.
Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin--a hormone with multiple functions.Front Neuroendocrinol. 2004;25:27-68.
Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review.Obes Rev. 2007;8:21-34.
Brennan AM, Mantzoros CS. Drug Insight: the role of leptin in human physiology and pathophysiology--emerging clinical applications.Nat Clin Pract Endocrinol Metab. 2006;2:318-327.
Roubos EW, Dahmen M, Kozicz T, Xu L. Leptin and the hypothalamo-pituitary-adrenal stress axis.Gen Comp Endocrinol. 2012;177:28-36.
Oswal A, Yeo G. Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity.Obesity (Silver Spring). 2010;18:221-229.
Price TO, Farr SA, Yi X, Vinogradov S, Batrakova E, Banks WA, Kabanov AV. Transport across the blood-brain barrier of pluronic leptin.J Pharmacol Exp Ther. 2010;333:253-263.
Coll AP, Yeo GS, Farooqi IS, O’Rahilly S. SnapShot: the hormonal control of food intake.Cell. 2008;135:572.e1-572.e2.
Himmerich H, Zimmermann P, Ising M, Kloiber S, Lucae S, Kunzel HE, Binder EB, Holsboer F, Uhr M. Changes in the hypothalamic-pituitary-adrenal axis and leptin levels during antidepressant treatment.Neuropsychobiology. 2007;55:28-35.
Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant.Proc Natl Acad Sci USA. 2006;103:1593-1598.
Liu J, Garza JC, Bronner J, Kim CS, Zhang W, Lu XY. Acute administration of leptin produces anxiolytic-like effects: a comparison with fluoxetine.Psychopharmacology (Berl). 2010;207:535-545.
Lawson EA, Miller KK, Blum JI, Meenaghan E, Misra M, Eddy KT, Herzog DB, Klibanski A. Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat.Clin Endocrinol (Oxf). 2012;76:520-525.
Jiménez I, Sobrino T, Rodríguez-Yáñez M, Pouso M, Cristobo I, Sabucedo M, Blanco M, Castellanos M, Leira R, Castillo J. High serum levels of leptin are associated with post-stroke depression.Psychol Med. 2009;39:1201-1209.
Pasco JA, Jacka FN, Williams LJ, Henry MJ, Nicholson GC, Kotowicz MA, Berk M. Leptin in depressed women: cross-sectional and longitudinal data from an epidemiologic study.J Affect Disord. 2008;107:221-225.
Milaneschi Y, Simonsick EM, Vogelzangs N, Strotmeyer ES, Yaffe K, Harris TB, Tolea MI, Ferrucci L, Penninx BW. Leptin, abdominal obesity, and onset of depression in older men and women.J Clin Psychiatry. 2012;73:1205-1211.
Milaneschi Y, Sutin AR, Terracciano A, Canepa M, Gravenstein KS, Egan JM, Vogelzangs N, Guralnik JM, Bandinelli S, Penninx BW. The association between leptin and depressive symptoms is modulated by abdominal adiposity.Psychoneuroendocrinology. 2014;42:1-10.
Jow GM, Yang TT, Chen CL. Leptin and cholesterol levels are low in major depressive disorder, but high in schizophrenia.J Affect Disord. 2006;90:21-27.
Westling S, Ahrén B, Träskman-Bendz L, Westrin A. Low CSF leptin in female suicide attempters with major depression.J Affect Disord. 2004;81:41-48.
Atmaca M, Tezcan E, Kuloglu M, Ustundag B. Serum leptin levels in obsessive-compulsive disorder.Psychiatry Clin Neurosci. 2005;59:189-193.
Emül HM, Serteser M, Kurt E, Ozbulut O, Guler O, Gecici O. Ghrelin and leptin levels in patients with obsessive-compulsive disorder.Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1270-1274.
Gecici O, Kuloglu M, Atmaca M, Tezcan AE, Tunckol H, Emül HM, Ustundag B. High serum leptin levels in depressive disorders with atypical features.Psychiatry Clin Neurosci. 2005;59:736-738.
Häfner S, Baumert J, Emeny RT, Lacruz ME, Thorand B, Herder C, Koenig W, Rupprecht R, Ladwig KH. Sleep disturbances and depressed mood: a harmful combination associated with increased leptin levels in women with normal weight.Biol Psychol. 2012;89:163-169.
Häfner S, Zierer A, Emeny RT, Thorand B, Herder C, Koenig W, Rupprecht R, Ladwig KH. Social isolation and depressed mood are associated with elevated serum leptin levels in men but not in women.Psychoneuroendocrinology. 2011;36:200-209.
Esel E, Ozsoy S, Tutus A, Sofuoglu S, Kartalci S, Bayram F, Kokbudak Z, Kula M. Effects of antidepressant treatment and of gender on serum leptin levels in patients with major depression.Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:565-570.
McKibben B. Ghrelin: The hunger hormone.Advanced Biochemistry. 2007;1-12.
Kojima M. Discovery of Ghrelin and its Physiological Function.J Med Sci. 2010;3:92-95.
Toska A, Saridi M, Rekleiti M, Wozniak G. Impact of Ghrelin and Adiponectin on Metabolic and Cardiovascular Effects.Int J Caring Sci. 2013;6:349-359.
Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake in obese as well as lean subjects.Int J Obes (Lond). 2005;29:1130-1136.
Schanze A, Reulbach U, Scheuchenzuber M, Groschl M, Kornhuber J, Kraus T. Ghrelin and eating disturbances in psychiatric disorders.Neuropsychobiology. 2008;57:126-130.
Gil-Campos M, Aguilera CM, Cañete R, Gil A. Ghrelin: a hormone regulating food intake and energy homeostasis.Br J Nutr. 2006;96:201-226.
Steiger A, Dresler M, Schüssler P, Kluge M. Ghrelin in mental health, sleep, memory.Mol Cell Endocrinol. 2011;340:88-96.
Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA. Ghrelin controls hippocampal spine synapse density and memory performance.Nat Neurosci. 2006;9:381-388.
Seoane LM, Al-Massadi O, Lage M, Dieguez C, Casanueva FF. Ghrelin: from a GH-secretagogue to the regulation of food intake, sleep and anxiety.Pediatr Endocrinol Rev. 2004;1 Suppl 3:432-437.
Andrews ZB. The extra-hypothalamic actions of ghrelin on neuronal function.Trends Neurosci. 2011;34:31-40.
Barim AO, Aydin S, Colak R, Dag E, Deniz O, Sahin I. Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment.Clin Biochem. 2009;42:1076-1081.
Schellekens H, Finger BC, Dinan TG, Cryan JF. Ghrelin signalling and obesity: at the interface of stress, mood and food reward.Pharmacol Ther. 2012;135:316-326.
Carlini VP, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin.Biochem Biophys Res Commun. 2004;313:635-641.
Nakashima K, Akiyoshi J, Hatano K, Hanada H, Tanaka Y, Tsuru J, Matsushita H, Kodama K, Isogawa K. Ghrelin gene polymorphism is associated with depression, but not panic disorder.Psychiatr Genet. 2008;18:257.
Kristenssson E, Sundqvist M, Astin M, Kjerling M, Mattsson H, Dornonville de la Cour C, Håkanson R, Lindström E. Acute psychological stress raises plasma ghrelin in the rat.Regul Pept. 2006;134:114-117.
Ochi M, Tominaga K, Tanaka F, Tanigawa T, Shiba M, Watanabe T, Fujiwara Y, Oshitani N, Higuchi K, Arakawa T. Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats.Life Sci. 2008;82:862-868.
Hansson C, Haage D, Taube M, Egecioglu E, Salomé N, Dickson SL. Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence.Neuroscience. 2011;180:201-211.
Spencer SJ, Xu L, Clarke MA, Lemus M, Reichenbach A, Geenen B, Kozicz T, Andrews ZB. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress.Biol Psychiatry. 2012;72:457-465.
Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress.Nat Neurosci. 2008;11:752-753.
Chuang JC, Zigman JM. Ghrelin’s Roles in Stress, Mood, and Anxiety Regulation.Int J Pept. 2010;2010:460549.
Kluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, Steiger A. Ghrelin plasma levels are not altered in major depression.Neuropsychobiology. 2009;59:199-204.
Matsuo K, Nakano M, Nakashima M, Watanuki T, Egashira K, Matsubara T, Watanabe Y. Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder.Brain Res. 2012;1473:185-192.
Rouach V, Bloch M, Rosenberg N, Gilad S, Limor R, Stern N, Greenman Y. The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.Psychoneuroendocrinology. 2007;32:693-702.
Ozsoy S, Besirli A, Abdulrezzak U, Basturk M. Serum ghrelin and leptin levels in patients with depression and the effects of treatment.Psychiatry Investig. 2014;11:167-172.
Kluge M, Schüssler P, Dresler M, Schmidt D, Yassouridis A, Uhr M, Steiger A. Effects of ghrelin on psychopathology, sleep and secretion of cortisol and growth hormone in patients with major depression.J Psychiatr Res. 2011;45:421-426.
Schmid DA, Wichniak A, Uhr M, Ising M, Brunner H, Held K, Weikel JC, Sonntag A, Steiger A. Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine.Neuropsychopharmacology. 2006;31:832-844.
Ishitobi Y, Kohno K, Kanehisa M, Inoue A, Imanaga J, Maruyama Y, Ninomiya T, Higuma H, Okamoto S, Tanaka Y. Serum ghrelin levels and the effects of antidepressants in major depressive disorder and panic disorder.Neuropsychobiology. 2012;66:185-192.
Kageyama K, Kumata Y, Akimoto K, Takayasu S, Tamasawa N, Suda T. Ghrelin stimulates corticotropin-releasing factor and vasopressin gene expression in rat hypothalamic 4B cells.Stress. 2011;14:520-529.
Kageyama K, Akimoto K, Yamagata S, Sugiyama A, Murasawa S, Watanuki Y, Tamasawa N, Suda T. Dexamethasone stimulates the expression of ghrelin and its receptor in rat hypothalamic 4B cells.Regul Pept. 2012;174:12-17.
Kalra SP, Ueno N, Kalra PS. Stimulation of appetite by ghrelin is regulated by leptin restraint: peripheral and central sites of action.J Nutr. 2005;135:1331-1335.
Wilkinson M, Brown R, Imran SA, Ur E. Adipokine gene expression in brain and pituitary gland.Neuroendocrinology. 2007;86:191-209.
Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain.J Comp Neurol. 2006;494:528-548.
Kishi T, Elmquist JK. Body weight is regulated by the brain: a link between feeding and emotion.Mol Psychiatry. 2005;10:132-146.