Leptin as a Neuroactive Agent

MELANIE L. ZUPANCIC, MD AND AMAN MAHAJAN, MD

Objective: To review the literature regarding the role of leptin in psychiatric disorders. Methods: A PubMed search was undertaken
using the following keywords: leptin, psychosis, affective disorders, alcohol, psychiatry, depression, dementia, and eating disorders.
The articles were restricted to the English language. Results: The role of leptin in psychiatric populations has been the subject of
increasing investigation. Basic science and clinical observations support a role for leptin in mediating cognition and reward processes.
The role of leptin in psychiatric illnesses characterized by cognitive deficits has gained increased attention in recent years. Leptin
deficiency and resistance have also been associated with eating disorders as well as affective, alcohol dependence, and psychotic
disorders. The mechanisms underlining these associations remain to be determined. Conclusions: Clinical research suggests an
important role of leptin in psychiatric illnesses. Given the morbidity associated with mental illness, clinical research on the role of
leptin and related novel therapeutic modalities is needed. Key words: leptin, eating disorders, cognition, dementia, psychosis,
depression, alcohol dependence.

AA = amyloid beta; AN = anorexia nervosa; BMI = body mass index; containing neurons (2,3). Leptin binding to Ob-R initiates a
BN = bulimia nervosa. cascade of events with ultimate inhibition of neuropeptide Y and
agouti-related proteinYcontaining neurons and food intake. In
addition, leptin acts to activate proopiomelanocortin neurons
INTRODUCTION resulting in the formation of >-melanocyte-stimulating hormone
and appetite suppression. Taken together, these actions result in
S ince the discovery of leptin by Zhang et al. (1) in 1994, its
role in metabolism and energy homeostasis has been ex-
tensively investigated (1Y3). Leptin is an adipocyte-derived
decreased energy consumption. Leptin levels have been found to
be high in many disease states associated with altered metabolism
including diabetes and obesity. In patients with these disorders,
hormone, and its levels generally parallel the amount of adi-
pose tissue present and are a reflection of fat stores. Leptin may leptin levels are found to be elevated, reflecting a state of leptin
resistance. Conversely, disorders characterized by a low body
play a role in various psychiatric disorders, particularly those
mass index (BMI) such as AN are associated with low leptin
such as anorexia nervosa (AN) and bulimia nervosa (BN) in
levels that rise during refeeding in parallel to BMI (15,16). While
which energy and metabolism are the focus of disease (4Y12).
leptin’s role in energy homeostasis came to be appreciated, an
However, little is known about the characteristics of leptin
interest emerged in its possibility as a therapeutic agent in obesity.
levels in various other psychiatric disorders. The observation of
However, studies to date have not demonstrated consistent effects
leptin in several brain areas related to affect and cognition,
of interventions targeting leptin in reducing obesity.
including the hypothalamus, hippocampus, and amygdala, has
sparked increased interest in this research area (2,13,14). The Leptin receptors have also been discovered in other brain
regions besides the hypothalamus including the amygdala, hip-
present review describes the results of investigations examining
pocampus, cerebellum, medulla, neocortex, basal ganglia, and
leptin in the following psychiatric disorders: AN, BN, alcohol
nucleus basalis of Meynert (13,14). The discovery of receptors
dependence, affective disorders, schizophrenia, and cognitive
outside the hypothalamus led to the speculation regarding lep-
impairment.
tin’s extra metabolic effects. For example, the presence of Ob-R
Leptin is found on the ob gene, and the leptin receptor (Ob-R)
in the hippocampus has lead investigators to examine the hor-
is encoded on the db gene (2). Alternative splicing yields six
mones’ role in memory and learning, whereas its presence in
isoforms differing in the intracellular C-terminal portion. The
Ob-Rb is the predominant isoform (2). Ob-R shows the greatest the amygdala led to the speculation about its role in affective
disorders. The following is a literature review summarizing
homology with cytokine receptors and acts via association with
the research findings regarding the role of leptin in psychiatric
janus tyrosine kinases. Leptin binds Ob-R in ventromedial hy-
disorders. Conceptually, the association of leptin with psychi-
pothalamus, arcuate nucleus, and dorsomedial hypothalamus, to
atric disorders relates both to its metabolic properties as in eat-
suppress food intake (2). Leptin has several neuronal targets
ing disorders and neurobiological functions as seen in disorders
within the hypothalamus to regulate food intake and body weight.
of reward circuits, affect, and cognition. This review deals with
These include the orexigenic neuropeptide Y and agouti-related
each of these associations separately.
proteinYcontaining neurons, and anorexigenic proopiomelano-
cortin and cocaine- and amphetamine-regulated transcriptY

From the Department of Internal Medicine, Division of Medicine/Psychiatry
(M.L.Z.), Department of Psychiatry (A.M.), Southern Illinois University School
of Medicine, Springfield, Illinois.
Address correspondence and reprint requests to Melanie L. Zupancic, MD,
Department of Internal Medicine, Division of Medicine/Psychiatry, PO Box
19636, Springfield, IL 62729. E-mail: mzupancic@siumed.edu
The authors report no conflicts of interest.
Received for publication July 7, 2010; revision received March 1, 2011.
DOI: 10.1097/PSY.0b013e31821a196f
METHODS
A literature search was undertaken using the following key words: leptin,
cognition, psychosis, affective disorders, psychiatry, depression, dementia,
alcohol, and eating disorders. The articles were restricted to the English
language. In the period from 1994 to October 2010, a total of 1221 articles
were identified using the initial selection criteria. Of these articles, 1169 were
excluded because they did not address the purposes of the present review.
The final number of articles was 52, divided over the following areas: AN
and BN (n = 10), alcohol dependence (n = 6), depression (n = 6), schizophrenia
(n = 1), and neurocognitive alterations (n = 23). The remaining six articles

Psychosomatic Medicine 73:407Y414 (2011) 407

0033-3174/11/7305Y0407
Copyright * 2011 by the American Psychosomatic Society

Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

Study
Beranova et al. (15)
Calandra et al. (4)
Brewerton et al. (5)
Monteleone et al. (6)
Monteleone et al. (7)
Hebebrand et al. (8)
Eckert et al. (9)
Grinspoon et al. (10)
Holtkamp et al. (11)
Nicolas et al. (17)
Rojdmark et al. (18)
Kiefer et al. (19)
Kraus et al. (20)
Wurst et al. (21)
408
Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
TABLE 1. Results of Human Studies of Leptin and Psychiatric Disorders
Diagnosis Sample Size
AN 10 female patients
10 healthy controls
AN/BN 24 female patients
12 weight-reduced controls
12 female controls with
normal weight
AN/BN 37 female patients
16 healthy female controls
AN/BN 89 female patients
38 healthy controls
AN/BN/binge eating disorder 42 female patients
25 healthy female controls
AN 23 female patients
AN 29 female patients
15 healthy controls with
normal weight
AN 22 female patients
23 healthy controls
AN 18 female patients
18 age-/sex-matched
controls
Alcohol dependence 60 active alcohol-dependent
patients
20 alcohol-dependent
patients with cirrhosis
20 abstinent alcohol-dependent
patients
60 healthy controls
Alcohol dependence 14 healthy subjects
(7 men and 7 women)
Alcohol dependence 78 alcohol-dependent inpatients
30 health controls
Alcohol dependence 102 alcohol-dependent
inpatients during withdrawal
Alcohol dependence 18 alcohol withdrawal patients
18 abstinent healthy controls
M. L. ZUPANCIC AND A. MAHAJAN
Findings
Leptin levels increased with increasing
weight during 6 weeks of refeeding.
Leptin levels in patients with anorexia are
lower than that in patients with BN and
controls and correlate with BMI. Leptin levels
in BN are not significantly different from that
in controls.
After controlling for body weight and BMI,
leptin levels are lower in BN than in normal
controls. Patients with comorbid BN and
AN did not differ in leptin levels from
those with BN only despite significantly
different BMI.
Leptin production decreased in BN patients
with longer duration of illness and greater
severity of binging/vomiting behavior
independent of body mass and weight.
Leptin decreased in underweight AN and
normal weight BN but increased in overweight
patients with binge-eating disorder.
Leptin levels during refeeding exceeding those
observed in healthy females matched for age,
BMI, and percentage of body fat.
Leptin levels in untreated AN patients were
significantly lower than in those in normal
body weight controls, and at the lowest
body weights, they uncouple from body
weight in a nonlinear fashion.
Leptin levels are highly correlated with weight
and percentage of body fat.
Threshold levels of leptin were determined
for increased gonadotropin secretion
and recovery of reproductive function.
Leptin levels are increased in a dose-dependent
manner in chronic alcohol-dependent
patients independent of nutritional status
or liver disease.
Leptin secretion is inhibited by moderate
amounts of alcohol.
Leptin levels significantly decreased during
14 days of withdrawal. Craving scores also
decreased significantly for 14 days. Body
mass corrected leptin levels were highly
correlated with self-rated craving scores
at the onset of withdrawal.
Leptin increased during a 10-day withdrawal,
and cravings decreased.
Acute intoxication has only a minor
influence on leptin levels in alcohol
detoxification patients.
(Continued on next page)
Psychosomatic Medicine 73:407Y414 (2011)
LEPTIN AS A NEUROACTIVE AGENT
Study
Kiefer et al. (22)
Jow et al. (23)
Kraus et al. (24)
Zeman et al. (25)
Westling et al. (26)
Atmaca et al. (27)
Atmaca et al. (28)
Venkatasubramanian
et al. (29)
Christman et al. (30)
Hassenstab et al. (31)
Dey et al. (32)
Psychosomatic Medicine 73:407Y414 (2011)
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TABLE 1. (Continued)
Diagnosis Sample Size
Alcohol dependence 160 detoxed alcohol-dependent
patients
Depression/schizophrenia 69 patients with MDD
78 patients with schizophrenia
51 healthy controls
Depression/schizophrenia 62 patients with MDD
42 patients with schizophrenia
64 healthy controls
Depression 38 women with
depressive disorders
38 healthy controls
Depression 72 suicide attemptors
Suicide 24 suicide attemptors
24 healthy controls
Bipolar disorder 16 patients with manic episodes
16 patients with BPAD I in
full remission
16 healthy controls
Schizophrenia 18 antipsychotic naive
patients with schizophrenia
Cognition 28 patients with diabetes
150 patients without diabetes
Cognition 73 patients (mean age, 60.4 y)
with metabolic syndrome
70 age- and education-matched
controls
Cognition 28 patients with diabetes
28 controls without diabetes
Findings
Leptin levels decreased significantly during
12 weeks of treatment with combination
of naltrexone and acamprosate versus
either agent alone or placebo. Increasing
leptin levels during the first month of the
treatment are associated with increased
cravings and decreased abstinence.
Leptin and cholesterol levels were low in
patients with MDD but high in patients
with schizophrenia.
Negative correlations were observed between
BDI scores, and serum cholesterol/leptin
levels were observed in MDD.
Positive correlations were observed between
serum cholesterol or leptin levels and length
of illness in schizophrenia.
Decreased leptin levels were observed in both
patient groups compared with controls
with patients with schizophrenia having
significantly lower levels than MDD
independent of BMI and medications.
Women with depressive disorders had higher
concentrations of leptin and lower insulin
sensitivity compared with healthy controls.
Women with MDD had lower CSF leptin levels
than non-MDD women despite similar BMI.
Leptin and cholesterol levels are significantly
lower in attemptors versus controls.
Patients with manic episodes and BPAD I in
remission had significantly lower leptin
levels compared with controls.
Negative correlations were observed between
YMRS and serum cholesterol or leptin levels in
patients with manic episodes.
Higher baseline leptin levels were correlated with
greater improvement in positive symptoms after
4 weeks of antipsychotic treatment.
Compared with controls, patients with diabetes
had lower brain-to-intracranial volume ratios
and poorer performance on measures of
working memory, processing speed, fluency,
and crystallized intelligence. Impairments in
processing speed and working memory
were associated with impairments in
instrumental activities of daily living.
Metabolic syndrome is associated with reductions
in recall, lower overall intellectual functioning,
and executive function.
Diabetics showed statistically significant
impairments in measures of attention, repetition,
and memory compared with healthy controls.
No differences in comprehension, naming,
construction, or calculation were observed.
The duration of diabetes, HbA1C, and
presence of neuropathy did not correlate
with cognitive function.
(Continued)
409
 M. L. ZUPANCIC AND A. MAHAJAN

TABLE 1. (Continued)

Study Diagnosis Sample Size Findings

Whittmer et al. (33) Cognition 6583 middle-aged adults After 3 decades of follow-up, central obesity
increased the risk of dementia independent
of age, race, education, diabetes, and
cardiovascular comorbidities.
Barrett-Connor et al. (34) Cognition 134 community-dwelling men For 20 years of follow-up, weight loss was
165 community-dwelling women found to precede dementia diagnosis.
Huang et al. (35) Cognition 59 HIV-positive men Lower CSF leptin levels and reduced leptin
uptake into CNS correlated with impaired
learning and memory performance after
adjusting for CD4 nadir, antiretroviral
treatment, and HIV RNA levels.
Holden et al. (36) Cognition 2871 well-functioning elderly Elderly subjects with higher leptin levels showed
subjects (aged 70Y79 y) lower rates of cognitive decline after adjusting for
age, race, sex, education level, hypertension,
diabetes, cardiac history, and baseline Modified
Mini-Mental State Examination.
Gunstad et al. (37) Cognition 35 older adults without neurologic Higher leptin levels were associated with poorer
or psychiatric histories performance on Trail-Making Test independent
of age, BMI, insulin levels, and sex.

AN = anorexia nervosa; BDI = Beck Depression Inventory; BMI = body mass index; BN = bulimia nervosa; BPAD = bipolar affective disorder; CNS = central
nervous system; CSF = cerebrospinal fluid; HbA1C = hemoglobin A1c; HIV = human immunodeficiency virus; MDD = major depressive disorder; RNA =
ribonucleic acid; YMRS = Young Mania Rating Scale.

dealt with basic science principles not specific to any psychiatric illness. Table 1
provides a summary of studies conducted in clinical samples (n = 30).
LEPTIN AND EATING DISORDERS
The potential role of leptin in eating disorders is intuitive given
the adipokine’s well-documented role in energy homeostasis
and metabolism. Several studies have examined leptin levels in
both AN and BN with heterogeneous findings. Calandra et al.
(4) found that females with anorexia had significantly lower
leptin concentrations compared with patients with BN and
healthy controls and this was a function of lower body weight.
Patients with bulimia had similar leptin levels compared with
controls despite poor nutritional behavior. Not surprisingly, a
positive correlation between leptin and BMI was observed (4).
Similarly, in a study of 10 women with BN and concurrent AN,
27 women with BN without concurrent AN, and 16 controls
without eating disorders, Brewerton et al. (5) found positive
correlations among leptin, BMI, weight, and percentage of
average body weight. However, leptin levels in BN patients
were lower than those in normal controls even after correcting
for BMI and weight. There was no difference between BN
patients with AN and without AN despite lower BMIs in those
patients with concurrent AN (5). These findings suggest that
abnormalities in leptin concentrations in patients with bulimia
cannot simply be explained by changes in body weight and may
be related pathophysiology of the disorder itself or long-term
nutritional aberrations. Monteleone et al. (6) found that un-
derweight patients with AN had lower leptin levels than patients
with BN and healthy controls. Patients with BN had lower
leptin concentrations compared with healthy controls despite
having no significant differences in body weight and BMI (6).
Furthermore, patients with BN were divided into two separate
groups: one with leptin levels comparable to that found in AN
patients and those with levels similar to healthy controls. The
two groups did not differ in age, BMI, body weight, maximal
and minimal previous body weights, cortisol, or prolactin. The
low leptin group had a significantly longer duration of illness
and a higher frequency of binge/vomiting episodes (6). Similar
to the data reported by Brewerton et al. (5), these findings
suggest that the relationship between leptin and bulimia may be
a function of disease chronicity and long-term complications of
nutritional aberrations. The role of additional factors besides
body weight contributing to lowered leptin levels in BN has
been hypothesized by others as well (7).
Several studies have documented significantly lower leptin
levels in AN compared with controls (8Y10). In addition, there
are data suggesting that the relationship between plasma leptin
and BMI becomes nonlinear at extremely low body weights (9).
Upon refeeding, leptin levels rise above that observed in con-
trols matched for BMI, suggesting a possible rebound effect
(8). Thus, in AN, the relationship between body mass and
leptin may not be linear. Secondary amenorrhea is a hallmark
feature of AN, and research indicates that restoration of leptin
levels may be required for normalization of gonadotropin
secretion (11,12).
LEPTIN AND ALCOHOL DEPENDENCE
In addition to acting on the hypothalamus to reduce food
intake, leptin also inhibits the mesolimbic reward circuit in-
volving motivation, desire, anticipation, and memory, associ-
ated with food consumption (3). Dopaminergic projections

410 Psychosomatic Medicine 73:407Y414 (2011)

Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
LEPTIN AS A NEUROACTIVE AGENT
from the ventral tegmental area to the nucleus accumbens
regulate these factors and are directly inhibited by leptin (2,3).
One theory of substance use disorders is that they result from
innate hypoactivation of the reward circuit. Given the leptin’s
inhibitory effect on the reward circuit, hyperleptinemia may be
a biologic risk factor for the development of such disorders. In
fact, elevated leptin levels have been associated with alcohol
dependence independent of BMI and nutritional status (17).
However, other studies have suggested that alcohol may have
an inhibitory effect on leptin secretion in healthy adults (18).
Kiefer et al. (19) found increased levels of leptin in alcohol-
dependent patients at the onset of withdrawal as compared with
healthy controls. The levels decreased during withdrawal and
were positively correlated with cravings (38). However, not all
studies have supported these findings (20,21). The conflicting
findings may be related to methodological differences and sex
differences of the populations studied. In addition, in a study
involving 160 alcohol-dependent patients, the combination
of naltrexone and acamprosate was associated with decreas-
ing leptin levels and higher rates of abstinence compared with
placebo. These effects were not noted with a single-agent
treatment, leading the authors to speculate that the leptin’s
lower effect of combination treatment may account for en-
hanced rates of abstinence (22).
LEPTIN AND DEPRESSION
The elevated rates of depression in insulin-resistant states
such as obesity and Type 2 diabetes lead one to speculate that
leptin may have a role in affective disorders. Animal studies
have supported this notion. Lu et al. (39) found that rats ex-
posed to chronic unpredictable stress had significantly lower
leptin levels compared with nonstressed controls. Decreased
sucrose preference is theorized to mimic the anhedonic state of
major depression. Lu et al. (39) found that rats exposed to
chronic unpredictable stress demonstrated lower sucrose pref-
erence relative to controls. This effect was reversed with leptin
administration. Leptin administration to nonstressed rats did
not increase sucrose preference, suggesting that leptin does not
promote sucrose preference in the absence of chronic stress
(39). The effects of leptin were hypothesized to be mediated by
increased expression of messenger ribonucleic acid in the
hippocampus and amygdala. Furthermore, intrahippocampal
infusions of leptin decreased immobility in a dose-dependent
manner during the forced swim test, which is an animal para-
digm for depression (39).
Low leptin levels have also been associated with depression
in humans (23,24) even after controlling for BMI. Conversely,
Zeman et al. (25) found elevated levels of leptin in 38 women
with depressive disorders compared with 38 healthy controls.
However, women with depressive disorders also had an ele-
vated insulin, C-peptide levels, and lower measures of insulin
sensitivity, suggesting insulin and leptin resistance. These data
suggest that it is not the absolute serum leptin concentration
but rather the ability of the hormone to induce an effect at the
receptor or postreceptor level, that is, correlated with mood.
Low levels of leptin have also been correlated with suicidality
Psychosomatic Medicine 73:407Y414 (2011)
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(26,27). Atmaca et al. (28) found that patients with Type I
bipolar affective disorder in remission and patients in mania
had significantly lower cholesterol and leptin levels than
healthy controls. Thus, the available evidence suggests that
leptin may have a role in affective disorders.
LEPTIN AND SCHIZOPHRENIA
It has long been established that the administration of anti-
psychotics can result in metabolic syndrome. Several studies
have also demonstrated elevated leptin levels in this popula-
tion. Although historically assumed to be the result of weight gain
and subsequent insulin and leptin resistance, more recent
data suggest that leptin may have a role in the prognosis of the
positive symptoms of schizophrenia. In a study of 18 never-
before-treated patients with schizophrenia, Venkatasubramanian
et al. (29) showed that elevated pretreatment leptin levels were
associated with a greater reduction in positive symptoms after
4 weeks of treatment with atypical antipsychotics. In addition,
Kraus et al. (24) demonstrated significantly lower leptin levels
in patients with schizophrenia relative to patients with depression
or healthy controls despite no difference in mean BMIs be-
tween groups. Leptin levels were independent of psychotropic
medications (24). Jow et al. (23) found that leptin levels corre-
lated positively with the length of illness. Although these
findings need to be replicated on a larger scale, the findings are
intriguing given previous observations of reduced hippocampal
volume in patients with schizophrenia and the increased hippo-
campal gray matter observed upon exogenous leptin adminis-
tration (40,41).
LEPTIN AND COGNITION
The observation of Ob-R in the hippocampus leads to the
speculation regarding leptin’s role in regulating memory and
learning. It has been observed that patients with disease states
characterized by leptin resistance including diabetes and meta-
bolic syndrome demonstrate cognitive deficits and are at greater
risk for subsequent dementia (30Y32). Furthermore, individuals
with central adiposity are at increased risk for later dementia
independent of age, sex, hypertension, diabetes, vascular dis-
ease, and BMI (33). Patients with Alzheimer demonstrate weight
loss before the onset of cognitive deficits independent of life-
style, depression, or other comorbidities (34).
Low cerebrospinal fluid leptin levels in men infected with
human immunodeficiency virus correlated with impaired learn-
ing and memory performance after adjusting for viral load, CD4
counts, and antiretroviral treatment exposure (35). Holden et al.
(36) examined 2871 well-functioning elderly patients aged 70
to 79 years prospectively for 4 years. After controlling for total
percentage of body fat and BMI, they found that those with
higher leptin levels had significantly less likelihood of cognitive
decline (36). Gunstand et al. (37) also found an association of
abnormal leptin levels with cognitive deficits in elderly subjects.
Lieb et al. (38) prospectively followed 785 adults with an aver-
age age of 79 years for 12 years and found that subjects in
the lowest quartile of baseline leptin levels had an absolute
411

Alzheimer disease risk of 25% versus 6% for those in the highest
quartile even after adjusting for comorbidites and BMI.
The mentioned findings suggest an association between
impaired cognitive functioning and absolute deficiency in leptin
or leptin resistance. Although leptin resistance is associated
with higher serum levels of the hormone, the effect of leptin
is attenuated. Thus, it seems that impaired cognition is not
a function of circulating leptin per se but rather its ability to
activate an appropriate response either at the receptor level or
through postreceptor modifications.
Several other studies have investigated leptin’s role in
memory and brain development. Steppan and Swick (42) found
that daily leptin administration for 2 weeks increased wet
and dry brain weights in leptin-deficient 4-week-old mice.
Furthermore, this increased mass was the result of increased
cell number supporting leptin’s role in neurogenesis (42). Ahima
et al. (43) examined the brain structure in leptin-deficient
4-week-old mice. They found reduced brain weight, immature
protein expression, reduced myelin basic protein, syntaxin-1,
synaptosomal-associated protein 25, and synaptobrevin ex-
pression. These deficiencies were corrected with leptin admin-
istration (43). Udagawa et al. (44) found increased neuronal
cell death in embryonic leptin-deficient mice.
Leptin has also been found to alter synaptic transmission
and possibly facilitate learning and memory. The hippocampus
mediates several forms of learning and memory. Several inves-
tigators have found that leptin facilitates long-term potentiation
and neuroplasticity via augmenting N-methyl-D-aspartic acid
receptor function and activation of calcium-calmodulin protein
kinase II in hippocampal CAI neurons (45Y47). Several investi-
gators have also demonstrated leptin’s role as a neuroprotective
agent in the hippocampus against ischemic insult as well as
excitotoxic and oxidative insults (48,49). The latter finding is
attributed to leptin’s activation of janus tyrosine kinase 2Ysignal
transducer and activator of transcription 3 and phosphatidylino-
sitol 3-kinase-AkT signaling pathways, induction of manganese
superoxide dismutase, and the antiapoptotic protein Bcl-xL (49).
Imaging studies also suggest a role for leptin in neuro-
protection. In a study involving 34 elderly subjects without
impaired fasting glucose, dementia, or metabolic syndrome,
Narita et al. (50) found that elevated leptin levels were posi-
tively correlated with gray matter volumes in the right hippo-
campus and bilateral cerebella. This suggests that leptin may
have a role in preventing the atrophy that occurs with aging.
In addition, Matochik et al. (40) found that exogenous leptin
administration to human subjects with genetic deficiencies
resulted in increased cerebral gray matter volume in the anterior
cingulated gyrus, inferior parietal lobule, and cerebellum, sug-
gesting a role of leptin in neurogenesis.
Based on these findings, it seems that leptin may be a me-
diator of cognitive functioning. Its role in the pathogenesis of
Alzheimer disease has been the subject of the recent study.
Although the pathogenesis of Alzheimer dementia is not en-
tirely clear, the extracellular accumulation of amyloid beta (AA)
and intracellular neurofibrillary tangles are thought to be cor-
nerstones of the neurodegenerative process. The production of
412
Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
M. L. ZUPANCIC AND A. MAHAJAN
AA is mediated by A-secretase cleavage of amyloid-A precursor
protein. Neurofibrillary tangles are intraneuronal aggregates of
highly phosphorylated tau protein and are probably mediated
by glycogen synthase kinase 3A. Such hyperphosphorylation
disrupts intracellular architecture leading to cell death. Fewlass
et al. (51) found that leptin reduced A-secretase activity in
neuronal cells and promoted apolipoprotein EYdependent
AA uptake in vitro, thus reducing its extracellular content.
Chronic administration of leptin to Alzheimer disease trans-
genic animals reduced the brain AA load that may have
implications for therapeutic interventions. In a series of exper-
iments, Greco et al. (52Y54) demonstrated that leptin reduces
tau phosphorylation and AA production through adenosine
monophosphateYactivated protein kinase pathways involving
inhibition of glycogen synthase kinase 3A.
Although the therapeutic potential of leptin in dementia
seems intuitive given the findings in basic science, systemic
controlled studies are needed in targeted clinical populations.
CONCLUSIONS AND FUTURE DIRECTIONS
Since the initial discovery of leptin, its extra metabolic
effects of leptin have become increasingly appreciated. Studies
have demonstrated possible roles of leptin in various psychi-
atric illnesses. The role of leptin in psychiatric illness likely
differs depending on the specific disorder. The abnormal levels
observed in eating disorders are probably a reflection of met-
abolic abnormalities, whereas those observed in affective and
cognitive disorders likely reflect leptin’s effects in brain struc-
tures associated with emotion and cognition such as the
hippocampus and the amygdala. However, one must be careful
in attempts to simplify complex systems. Although it may be
intuitive to assume the alterations in leptin levels associated
with AN and BN are simply a reflection of metabolic dis-
turbances, it is important to remember that these disorders are
also associated with considerable cognitive distortions and
abnormal thought processes. In addition, affective disorders
also have a noted cognitive component. Leptin plays a role in
neurogenesis and is therefore a likely candidate in the regula-
tion of the neural structures involved in the processing of both
external and internal stimuli relevant to cognition. It is possible
that leptin’s role in cognition ultimately leads to disturbances in
affect, reward perception, and reality testing.
Not one but multiple common final pathways play a role in
linking leptin alterations with the various psychiatric disorders
discussed in this review. The factors involved in leptin syn-
thesis, secretion, and metabolism are complex and subject to
various stages of regulation. How these regulatory steps man-
ifest in psychiatric illness is far from clear.
Although basic science has come a long way in eliciting the
cellular mechanisms underlining the effects of leptin on neu-
ropsychiatric aspects of illness, more research on the clinical
implications of leptin in psychiatric disorders is needed. While
the appreciation for the comorbidity of psychiatric disorders
and medical conditions in which metabolic processes play a
role increases, it may be important to develop novel therapeutic
interventions targeting leptin-related processes. Future studies
Psychosomatic Medicine 73:407Y414 (2011)
LEPTIN AS A NEUROACTIVE AGENT
are needed to further explore leptin’s role in cognitive processes
associated with psychiatric illness not traditionally conceptu-
alized as cognitive disorders such as schizophrenia and de-
pression. In addition, research examining the role of leptin in
specific affective domains such as anhedonia would be helpful
in clarifying the high comorbidity observed between disorders
traditionally believed to be related to reward circuit dysfunction
such as alcohol dependence and mood disorders also associated
with alterations in the ability to experience pleasure. Finally,
the well-established link between mood disorders and medical
illness associated with leptin resistance such as diabetes war-
rants further investigation as well as the association with states
of leptin resistance such as obesity with later onset dementia.
A better understanding of the role of leptin in psychiatric illness
may establish a framework on which future therapeutic mo-
dalities may be developed.
REFERENCES
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.
Positional cloning of the mouse obese gene and its human homologue.
Nature 1994;372:425Y32.
2. Harvey J. Leptin regulation of neuronal excitability and cognitive function.
Curr Opin Pharmacol 2007;7:643Y7.
3. Morrison CD. Leptin signaling in brain: a link between nutrition and
cognition? Biochim Biophys Acta 2009;1792:401Y8.
4. Calandra C, Musso F, Musso R. The role of leptin in the etiopathogenesis
of anorexia nervosa and bulimia. Eat Weight Disord 2003;8:130Y7.
5. Brewerton TD, Lesem MD, Kennedy A, Garvey WT. Reduced plasma
leptin concentrations in bulimia nervosa. Psychoneuroendocrinology 2000;
25:649Y58.
6. Monteleone P, Martiadis V, Colurico B, Maj M. Leptin secretion is related
to chronicity and severity of illness in bulimia nervosa. Psychosom Med
2002;64:874Y9.
7. Monteleone P, Di Lieto A., Totorella A, Longobardi N, Maj M. Circulating
leptin in patients with anorexia nervosa, bulimia nervosa or binge-eating
disorder: relationship to body weight, eating patterns, psychopathology
and endocrine changes. Psychiatry Res 2000;94:121Y9.
8. Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, Ziegler A,
Warnke A, Rascher W, Remschmidt H. Leptin levels in patients with an-
orexia nervosa are reduced in the acute stage and elevated upon short-term
weight restoration. Mol Psychiatry 1997;2:330Y4.
9. Eckert ED, Pomeroy C, Raymond N, Kohler PF, Thuras P, Bower CY.
Leptin in anorexia nervosa. J Clin Endocrinol Metab 1998;83:791Y4.
10. Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, Ma Z,
Vignati L, Bowsher R, Herzog D, Klibanski A. Serum leptin levels in
women with anorexia nervosa. J Clin Endocrinol Metab 1996;81:3861Y3.
11. Holtkamp K, Mika C, Grzella I, Heer M, Pak H, Heberbrand J,
Herpertz-Dahlmann B. Reproductive function during weight gain in an-
orexia nervosa. Leptin represents a metabolic gate to gonadotropin secre-
tion. J Neural Transm 2002;110:427Y35.
12. Bluher S, Mantzoros CS. The role of leptin in regulating neuroendocrine
function in humans. J Nutr 2004;9:2469SY74S.
13. Burguera B, Couce M, Long J, Lamsam J, Laakso K, Jense M, Parisi J,
Lloyd R. The long form of the leptin receptor (OB-Rb) is widely expressed
in the human brain. Neuroendocrinology 2000;61:187Y95.
14. Couce ME, Burguera B, Parisi JE, Jenson MD, Lloyd RV. Localization of
leptin receptor in human brain. Neuroendocrinology 1997;66:145Y50.
15. Beranova L, Sediackova D, Kopeckova J, Hainer V, Papezova H,
Kvasnickova H, Nedvidkova J. Neuropeptide Y, ghrelin, and leptin plasma
levels in anorexia nervosa patients and their changes during six week
refeeding. Vnitr Lek 2009;55:925Y8.
16. Oswiecimska J, Siora K, Geisler G, Broll-Waska K. Prospective evaluation
of leptin and neuropeptide Y (NPY) serum levels in girls with anorexia
nervosa. Neuro Endocrinol Lett 2005;26:301Y4.
17. Nicolas JM, Fernandez-Sola J, Fatjo F, Casamitjana R, Bataller R,
Sacanella E, Tobı́as E, Badı́a E, Estruch R. Increased circulating leptin
levels in chronic alcoholism. Alcohol Clin Exp Res 2001;25(1):83Y8.
Psychosomatic Medicine 73:407Y414 (2011)
Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
18. Rojdmark S, Calissendorft J, Brismar K. Alcohol ingestion decreases
both diurnal and nocturnal secretion of leptin in healthy individuals. Clin
Endocrinol (Oxf) 2001;55:639Y47.
19. Kiefer F, Jahn H, Jaschinski M, Holzbach R, Wolf K, Naber D,
Wiedemann K. Leptin: a modulator of alcohol craving? Biol Psychiatry
2001;49:782Y7.
20. Kraus T, Reulbach U, Bayerlein K, Mugele B, Hillemacher T, Sperling W,
Kornhuber J, Bleich S. Leptin is associated with craving in females with
alcoholism. Addict Biol 2004;9:213Y9.
21. Wurst FM, Bechtel G, Forster S, Wolfersdorf M, Huber P, Scholer A,
Pridzun L, Alt A, Seidl S, Dierkes J, Dammann G. Leptin levels of alco-
hol abstainers and detoxification patients are not different. Alcohol 2003;
38:364Y8.
22. Kiefer F, Jahn H, Otte C, Demiralay C, Wolf K, Wiedemann K. Increas-
ing leptin precedes craving and relapse during pharmacological absti-
nence maintenance treatment of alcoholism. J Psychiatr Res 2005;39:
545Y51.
23. Jow GM, Yang TT, Chen CL. Leptin and cholesterol levels are low in major
depressive disorder, but high in schizophrenia. J Affect Disord 2006;
90:21Y7.
24. Kraus T, Haack M, Schuld A, Hinze-Selch D, Pollmacher T. Low leptin
levels but normal body mass indices in patients with depression or
schizophrenia. Neuroendocrinology 2001;73:243Y7.
25. Zeman M, Jirak R, Jachymova M, Vecka M, Tvrzicka E, Zak A. Leptin,
adiponectin, leptin to adiponectin ratio and insulin resistance in depressive
women. Neuro Endocrinol Lett 2009;30:387Y95.
26. Westling S, Ahren B, Traskman-Bendz L, Westrin A. Low CSF leptin
in female suicide attempters with major depression. J Affect Disord 2004;
81:41Y8.
27. Atmaca M, Kuloglu M, Tezcan E. Serum leptin and cholesterol values in
suicide attempters. Neuropsychopharmacology 2002;45:124Y7.
28. Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Bayik Y. Serum leptin and
cholesterol levels in patients with bipolar disorder. Neuropsychobiology
2002;46:176Y9.
29. Venkatasubramanian G, Arasappa R, Christopher R, Gangadhar B.
Neuropharmacology of schizophrenia: is there a role for leptin? Clin Chem
Lab Med 2010;48:895Y6.
30. Christman AL, Vannorsdall TD, Pearlson GD, Hill-Briggs F, Schretien DJ.
Cranial volume, mild cognitive deficits, and functional limitations as-
sociated with diabetes in a community sample. Arch Clin Neuropsychol
2010;25:49Y59.
31. Hassenstab JJ, Sweat V, Bruehl H, Convit A. Metabolic syndrome is as-
sociated with learning and recall impairment in middle age. Dement
Geriatr Cogn Disord 2010;29:356Y62.
32. Dey J, Misra A, Desai NG, Mahapatra AK, Padma MV. Cognitive function
in younger type II diabetes. Diabetes Care 1997;20:32Y5.
33. Whittmer RA, Gustafson DR, Barrett-Connor E, Hann M, Gunderson EP,
Yaffe K. Central obesity and increased risk of dementia more than three
decades later. Neurology 2008;71:1057Y64.
34. Barrett-Connor E, Edlesteing SL, Corey-Bloom J, Widerholt WC. Weight
loss precedes dementia in community-dwelling older adults. J Am Geriatr
Soc 1996;44:1147Y52.
35. Huang JS, Letendre S, Marqui Beck J, McCutchan JA, Grant I, Ellis R.
Low CSF leptin levels are associated with worse learning and memory
performance in HIV-infected men. J Neuroimmune Pharmacol 2007;2:
352Y8.
36. Holden KF, Lindquist K, Tylavsky F, Rosan C, Harris T, Yaffe K. Serum
leptin level and cognition in the elderly: findings from the Health ABC
study. Neurobiol Aging 2009;30:1483Y9.
37. Gunstad J, Spitznagel M, Keary T, Glickman E, Alexander T, Karrer J,
Stanek K, Reese L, Juvancic-Heltzel J. Serum leptin levels are associated
with cognitive function in older adults. Brain Res 2008;1230:233Y6.
38. Lieb W, Beiser A, Vasan R, Tan ZS, Au R, Harris TB, Roubenoff R,
Auerbach S, DeCarli C, Wolf PA, Seshadri S. Association of plasma leptin
levels with incident Alzheimer disease and MRI measures of brain aging.
JAMA 2009;302:2565Y72.
39. Lu X, Kim C, Frazer A, Zhang W. Leptin: a potential novel antidepressant.
Proc Natl Acad Sci U S A 2006;103:1593Y8.
40. Matochik J, London E, Yildiz B, Ozata M, Caglayan S, DePaoli A,
Wong ML, Licinio J. Effect of leptin replacement on brain structure
in genetically leptin deficient adults. J Clin Endocrinol Metab 2005;90:
2851Y4.
41. Tamminga C, Stan A, Wagner A. The hippocampal formation in schizo-
phrenia. Am J Psychiatry 2010;167:1178Y93.
413

42. Steppan CM, Swick AG. A role for leptin in brain development. Biochem
Biophys Res Commun 1999;256:600Y2.
43. Ahima RS, Bjorbaek C, Osei S, Flier JS. Regulation of neuronal and glial
proteins by leptin: implications for brain development. Endocrinology
1999;140:2755Y62.
44. Udagawa J, Nimura M, Kagohashi Y, Otani H. Leptin deficiency causes
pycnotic change in fetal cingulated cortical cells. Congenit Anom (Kyoto)
2006;46:16Y20.
45. Shanley LJ, Irving AJ, Harvey J. Leptin enhances NMDA receptor func-
tion and modulates hippocampal synaptic plasticity. J Neurosci 2001;
21:186.
46. Oomura Y, Hori N, Shiraishi T, Fukunage K, Takeda H, Tsuji M,
Matsumiya T, Ishibashi M, Aou S, Li X, Kohno D, Uramura K, Sougawa H,
Yada T, Wayner MJ, Sasaki K. Leptin facilitates learning and memory
performance and enhances hippocampal CA1 long-term potentiation and
CaMK II phosphorylation in rats. Peptides 2006;27:2738Y49.
47. Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of
long-term potentiation and spatial memory in leptin receptor-deficient
rodents. Neuroscience 2002;113:607Y15.
414
Copyright © 2011 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.
M. L. ZUPANCIC AND A. MAHAJAN
48. Zhang F, Chen J. Leptin protects hippocampal CA1 neurons against is-
chemic injury. J Neurochem 2008;107:578Y87.
49. Gou Z, Jiang H, Xu X, Duan W, Mattson MP. Leptin-mediated cell survival
signaling in hippocampal neurons mediated by JAK STAT3 and mito-
chondrial stabilization. J Biol Chem 2008;283:1754Y63.
50. Narita K, Kosaka H, Okazawa H, Murata T, Wada Y. Relationship between
plasma leptin level and brain structure in elderly: a voxel-based morpho-
metric study. Biol Psychiatry 2009;65:992Y4.
51. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Texapsidis N.
Obesity-related leptin regulates Alzheimer’s Abeta. FASEB J 2004;18:1870Y8.
52. Greco SJ, Sarkar S, Casadesus G, Zhu X, Smith M, Ashford JW, Jonston JM,
Tezapsidis N. Leptin inhibits glycogen synthase kinase-3beta to prevent tau
phosphorylation in neuronal cells. Neursci Lett 2009;455:191Y4.
53. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N. Leptin regulates tau
phosphorylation and amyloid through AMPK in neuronal cells. Biochem
Biophys Res Commun 2009;380:98Y104.
54. Greco SJ, Sarkar S, Johnston JM, Tezapsidis N. Leptin reduces Alzheimer’s
disease-related tau phosphorylation in neuronal cells. Biochem Biophys
Res Commun 2008;376:536Y41.
Psychosomatic Medicine 73:407Y414 (2011)