Neurobiology of Disease 72 (2014) 6171

Contents lists available at ScienceDirect

Neurobiology of Disease
journal homepage: www.elsevier.com/locate/ynbdi

Review

Neuroprotective effects of leptin in the context of obesity and

metabolic disorders
Cecilia Davis, Jeremy Mudd, Meredith Hawkins
Diabetes Research Center, Albert Einstein College of Medicine, USA

a r t i c l e

i n f o

Article history:
Received 14 January 2014
Revised 9 April 2014
Accepted 21 April 2014
Available online 26 April 2014
Keywords:
Leptin
Neurodegeneration
Obesity
Diabetes
Leptin resistance
Metabolic disorder

a b s t r a c t
As the population of the world ages, the prevalence of neurodegenerative disease continues to rise, accompanied
by increases in disease burden related to obesity and metabolic disorders. Thus, it will be essential to develop
tools for preventing and slowing the progression of these major disease entities. Epidemiologic studies have
shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal
models have provided insights into the complex relationships between these conditions. Experimentally, the
fat-derived hormone leptin has been shown to act as a neuroprotective agent in various animal models of dementia, toxic insults, ischemia/reperfusion, and other neurodegenerative processes. Specically, leptin minimizes
neuronal damage induced by neurotoxins and pro-apoptotic conditions. Leptin has also demonstrated considerable promise in animal models of obesity and metabolic disorders via modulation of glucose homeostasis and
energy intake. However, since obesity is known to induce leptin resistance, we hypothesize that resistance to
the neuroprotective effects of leptin contributes to the pathogenesis of obesity-associated neurodegenerative
diseases. This review aims to explore the literature pertinent to the role of leptin in the protection of neurons
from the toxic effects of aging, obesity and metabolic disorders, to investigate the physiological state of leptin
resistance and its causes, and to consider how leptin might be employed therapeutically in the prevention and
treatment of neurodegenerative disease.
2014 Elsevier Inc. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . .
Alzheimer's disease and associated metabolic dysfunction .
Parkinson's disease and associated metabolic dysfunction .
Leptin action in the central nervous system (CNS) . . . . . . .
Leptin receptor isoforms and animal models of leptin inactivity .
Leptin and the blood brain barrier . . . . . . . . . . . . . .
Mechanisms of pro-survival and neuroprotective effects of leptin
Leptin action in animal models of neurodegenerative disease . .
Alzheimer's disease . . . . . . . . . . . . . . . . . .
Parkinson's disease . . . . . . . . . . . . . . . . . . .
Leptin, obesity and neurodegeneration . . . . . . . . . . . .
Clinical applications for leptin . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction

Corresponding author at: Belfer Building, Room 709, Albert Einstein College of
Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Available online on ScienceDirect (www.sciencedirect.com).

http://dx.doi.org/10.1016/j.nbd.2014.04.012
0969-9961/ 2014 Elsevier Inc. All rights reserved.

As the general population progressively ages, the prevalence of obesity, metabolic disease, and neurodegenerative disease continues to rise.
Neurodegenerative diseases belong to a class of diseases that appears to
be associated with age and obesity. Specically, Parkinson's disease and

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C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

Alzheimer's disease together have a prevalence of about three percent

at age 65, but by age 95 the prevalence rises to 55% (Alves et al., 2008;
Wang and Ding, 2008). Concurrent with the population-wide rise in
neurodegenerative disease is an increased prevalence of obesity,
which appears to be etiologically associated with neurodegeneration.
The World Health Organization estimates that in 2008 35% of adults
aged 20 and above were overweight, while 11% of this population was
obese (WHO, 2013). Obesity is associated with a wide array of deleterious consequences, including cardiovascular disease, type 2 diabetes,
dyslipidemia, sleep apnea, liver disease, obesity-related cancers, osteoarthritis, and psychological problems (Dixon, 2010). There is also growing evidence to suggest that obesity is a risk factor for the development
of dementia.
A potential therapeutic option supported by basic science research
for all of these inter-related pathological states is the adipokine leptin.
Leptin is an endogenous hormone produced most notably by adipose
tissue in direct proportion to fat mass (Klein et al., 1996). Leptin has
been shown to promote neuronal survival in pro-apoptotic environments and also to attenuate neuronal damage in animal models of
neurodegenerative disease. Leptin has also been implicated for its
mechanistic importance and potential therapeutic use in various
obesity-associated metabolic diseases, including lipodystrophy and
type 2 diabetes. Although obesity is associated with elevated leptin
levels, it also confers a state of leptin resistance, such that the neuroprotective effects of leptin are likely to be attenuated. Given that obesity is
both a common predating symptom and risk factor for metabolic and
neurodegenerative diseases, efforts to elucidate the therapeutic potential
of leptin for these two types of disease require a thorough understanding
of the mechanism of leptin signaling within both the endocrine and
nervous systems.
Obesity is a condition in which an excess of fat mass accumulates to
the point that it has a negative impact on the health of an individual. A
meta-analysis performed by Gorospe and Dave suggested that BMI may
be an independent risk factor for dementia after controlling for such
other well-known risk factors as age, gender, smoking, comorbidities,
and APOE-4 level (Gorospe and Dave, 2007). In fact, strong evidence
suggests that mid-life obesity is a risk factor for later-life development
of dementia (Hassing et al., 2009; Kivipelto et al., 2005; Whitmer
et al., 2005, 2008; Xu et al., 2011), specically in the form of Parkinson's
disease (Abbott et al., 2002), Alzheimer's disease (Hassing et al., 2009;
Kivipelto et al., 2005; Whitmer et al., 2007; Xu et al., 2011) and vascular
dementia (Hassing et al., 2009; Whitmer et al., 2007; Xu et al., 2011).
Not only is obesity a risk factor for the development of dementia
later in life, but it has also been found to be associated with lower
brain volumes (Ward et al., 2005), decreased gray matter density
(Pannacciulli et al., 2006), and lower cognitive function in middle-age
individuals (Elias et al., 2003, 2005). Elias et al. found that obesity was
related to cognitive decits in men but not women who participated
in the Framingham Heart Study after controlling for other risk factors,
including age, education, occupation, smoking behavior, and diabetes
mellitus (Elias et al., 2003, 2005). Wolf et al. found that both men and
women in the Framingham Offspring Cohort with the highest proportion of central obesity as measured by WaistHip ratio had signicantly
lower scores in cognitive testing (Wolf et al., 2007).
Alzheimer's disease and associated metabolic dysfunction
Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in neurological decits including memory loss and diminished cognitive function. Using 2010 United States Census data, Hebert
et al. estimated that 4.7 million Americans aged 65 or older suffered
from the disease, making it the most common neurological condition
in the United States (Hebert et al., 2013). By these same statistics, prevalence of AD in the US is expected to increase to 13.8 million by 2050,
with a prevalence of over 7 million individuals projected in the above85 age bracket. Current treatment modalities for the disease have

been shown to be only marginally effective, demonstrating benet in

managing symptoms and slowing of cognitive decline but not in global
disease progression (Rountree et al., 2009).
Signicant evidence points toward an association between risk of
development of Alzheimer's disease and such factors as excess body
weight at midlife, sedentary lifestyle, and a fat-rich, sugar-rich diet
(Cai et al., 2012; Farris et al., 2003; Mayeux and Stern, 2012; Simons
et al., 2006). Such a high-fat diet is thought to modulate changes to
hippocampal function via glucotoxicity (the toxic effects of increased
glucose availability) or disrupted insulin signaling, suggesting a potential connection between obesity and AD (Cai et al., 2012). Patients
with diabetes have been found to have two-fold greater risk of developing AD than patients without the disease, while patients with type 2
Diabetes and the ApoE4 allele are at a ve-fold greater risk of developing
AD than their counterparts without either of those conditions (Ott et al.,
1999; Peila et al., 2002). The association between hyperglycemia and
development of AD is strong, as glucose administration is directly correlated to the cleavage of tau a microtubule-stabilizing protein found
abundantly in the axons of neurons of the CNS that is widely accepted
as a predecessor of AD pathology (Kim et al., 2009). Glucose levels are
also positively correlated with apoptosis in the db/db mouse, which,
due to a premature stop codon mutation that renders the leptin receptor
(Ob-Rb) non-functional, exhibits an obese phenotype and characteristics
that qualify it as an effective model for type 2 diabetes (Chen et al., 1996;
Kim et al., 2009). According to a 2004 review of the Mayo Clinic
Alzheimer Disease Patient Registry records, more than 80% of the AD
patients were affected with type 2 DM or impaired fasting glucose
(Janson et al., 2004). Recent studies also indicate a connection between
low-grade chronic inammation associated with Metabolic Syndrome
and cognitive impairment preceding AD (Misiak et al., 2012). Together
these ndings suggest a connection between AD and sequelae associated
with metabolic dysfunction.
Parkinson's disease and associated metabolic dysfunction
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Epidemiological studies using
2010 US census estimates have estimated that 630,000 Americans
were living with diagnosed PD in 2010, with a prevalence of 12% of
the population above the age of 65 and 45% above the age of 85
(Kowal et al., 2013). The clinical presentation of PD typically consists
of bradykinesia, resting tremor, rigidity, and gait instability (Cai et al.,
2012). Parkinson's disease is primarily a disorder of motor function
characterized by signicant loss of dopaminergic neurons in the parscompacta of the substantia nigra by an unknown mechanism. The low
levels of expression of brain-derived neurotrophic factor (BDNF), a
critical neuronal growth factor found in the central and peripheral
nervous system (Mogi et al., 1999; Parain et al., 1999), in the substantia
nigra and the relative lack of dopaminergic neurons in PD patients and
mouse models suggest the critical role played by BDNF in normal development of those neurons (Baquet et al., 2005; Kohno et al., 2004). While
treatments for Parkinson's disease are more advanced and effective
than treatments for Alzheimer's, patients with PD still consistently
progress to end-stage disease.
Paradoxically, while midlife adiposity and consumption of a
carbohydrate-rich diet have been found to predict subsequent onset of
Parkinson's disease later in life (Abbott et al., 2002, 2003), metabolic
dysfunction in Parkinson's patients is generally associated with weight
loss upon disease onset, as well as evidence of alteration in glucose
homeostasis and insulin signaling. Although PD patients do not exhibit
reduced energy intake, they typically lose signicant weight from the
illness both before and after diagnosis and present lower BMI on
average than their age-matched normal controls (Abbott et al., 1992;
Beyer et al., 1995; Chen et al., 2003). In PD patients who experience
unintentional weight loss, circulating leptin levels have been found to
be lower than in weight-stable PD patients, with lowered leptin levels

C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

consistent with reduced body fat (Evidente et al., 2001). The weight loss
associated with PD would then result in less stored adipose, and thus
lowered serum leptin levels. This scenario is an example of the association between low leptin levels in the brain and pathogenesis of neurodegenerative disease. Additional studies have provided evidence of an
association between type 2 diabetes and PD. Wang et al. discovered
that mouse models of T2DM exhibit increased accumulation of -synuclein stress and neuroinammation in the midbrain when challenged
with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) a neurotoxin used to mimic cell death caused by PD suggesting that T2DM
mice are more likely to develop PD-associated dopaminergic cell
death than their non-diabetic counterparts (Wang et al., 2014).
Collectively, these ndings demonstrate the signicant, multidirectional interactions between metabolic disorders and neurodegenerative diseases.
Leptin action in the central nervous system (CNS)
Leptin action on the hypothalamus to provide a satiety signal was
the rst of the hormone's functions to be reported (Wurtman, 1996).
Since then, many additional functions of leptin have been dened that
are mediated through activating areas of the hypothalamus. These
other roles include anorectic signaling to the hypothalamus to regulate
energy balance (Myers et al., 2008), as well as partial regulation of reproductive function and bone metabolism (Ducy et al., 2000; Moschos
et al., 2002). More recently, the hypothalamus has been implicated in
mediating other central actions of leptin, specically in stimulation of
sympathetic nerve activity (Rahmouni and Morgan, 2007).
Other regions of the brain have been identied as areas that respond
to leptin (Leshan et al., 2006). In the hippocampus, leptin has been
shown to be important in modulating neuroplasticity (Harvey, 2007;
Oomura et al., 2006; Shanley et al., 2001), which has interesting implications for Alzheimer's disease (Carro, 2009). In the ventral tegmental
area, leptin, in conjunction with insulin, works with the brain's reward
system to reinforce eating behavior (Figlewicz et al., 2007). Widespread
leptin action has also been implicated in neural development, and
abnormal fetal or infant leptin levels are hypothesized to be risk factors
for development of metabolic disorders in adulthood (Louis and Myers,
2007; Udagawa and Otani, 2007).
Metabolic states such as obesity and starvation confer resistance to
the central actions of leptin, rendering the individual unresponsive to
the endogenous anorexic leptin signal, a biomarker of leptin action.
Ongoing research is investigating the various states of leptin resistance
and determining whether the central actions of leptin are globally or
selectively impaired in this resistant state (Enriori et al., 2011). Interestingly, it has been shown that the neuroprotective effects of leptin are
diminished in an environment of obesity (Johnston et al., 2011),
which has important clinical ramications for the expanding obesity
epidemic.
Leptin receptor isoforms and animal models of leptin inactivity
Six isoforms of the leptin receptor (Elmquist et al., 1998) have been
isolated in different areas of the brain, all performing different functions
(Bjorbak et al., 1998; Elmquist et al., 1998). The long form (Ob-Rb) is
predominantly responsible for activating multiple signal transduction
systems, while the short forms (Ob-Ra, Ob-Rc-f) of the leptin receptor
are responsible for bioavailability of leptin in the brain and mediation of
leptin crossing the bloodbrain barrier (BBB). It is critical to understand
the signal transduction pathways activated upon leptin binding to the
long form of its receptor, given that leptin provides an essential survival
signal to cells exposed to pro-apoptotic conditions. As summarized by
Zhang et al. (Zhang et al., 2007), after binding leptin, the leptin Ob-Rb
receptor forms a homodimer which results in autophosphorylation
and activation of Janus tyrosine kinase 2 (Jak2). Activated Jak2 can phosphorylate three sites of the intracellular domain of the leptin receptor,

63

thereby recruiting more components of the leptin signaling cascade.

The end result of leptin receptor binding is the activation of several
major signaling systems, most notably the STAT3, MEK/ERK, and PI3K/
Akt pathways (C. Chen et al., 2006; Frhbeck, 2006; Guo et al., 2008).
These pathways have been shown to play major roles in cell cycle regulation and in prevention of apoptosis in neural tissue as well as in other
tissue types (Arthur et al., 2006; Berra et al., 1998; Lee et al., 2005; Li
et al., 2009; Murase et al., 2012).
ob/ob and db/db mice are classic animal models of defective leptin
action and have been studied extensively in obesity research. ob/ob
mice are unable to produce functional leptin due to a nonsense mutation in the leptin gene (Zhang et al., 1994). As described earlier, db/db
mice have a frameshift mutation in the leptin receptor gene that results
in an early stop codon, leaving the receptor without a transmembrane
sequence (Lee et al., 1996). Both animal models have normal weights
at birth but go on to develop hyperphagia, morbid obesity, insulin resistance and glucose intolerance leading to frank diabetes mellitus
(Lee et al., 1996; Zhang et al., 1994). Koletsky rats, meanwhile,
are obese with decreased cerebrospinal uid (CSF) leptin levels
(Kastin et al., 1999) due to a mutation in the short form of the leptin receptor, Ob-Ra, expressed in the microvessels of the brain. The obese
phenotype of the Koletsky rats resembles the phenotype of the ob/ob
or db/db mice (Kastin et al., 1999). Because leptin is unable to exert its
Ob-Rb-mediated anorectic effect in any of these genotype models,
each model exhibits a phenotype of central leptin inactivity, resulting
in obesity.
Leptin and the blood brain barrier
Most known functions of leptin within the central nervous system
are presumably mediated by leptin produced in the periphery. However, leptin has also been shown to be produced in the brain itself (Morash
et al., 1999; Wiesner et al., 1999), although it is currently unknown
whether brain-derived leptin could act locally in an autocrine or paracrine manner. Since fat-derived leptin is likely responsible for most or
all of leptin-mediated central effects, leptin must be able to traverse
the blood brain barrier (BBB) to mediate its effects on the CNS. Ob-Ra
and Ob-Rc short form leptin receptor isoforms have both been shown
to be highly expressed in the microvessels of the brain and are believed
to mediate BBB transport of leptin (Wu-Peng et al., 1997). A functional
defect in the Ob-Ra short-form leptin receptor in the Koletsky rat
model demonstrates the importance of BBB transport to the biological
activity of leptin.
An interesting phenomenon is observed with respect to the BBB's
permeability to leptin. High triglyceride levels have been shown to
decrease leptin transport across the BBB (Banks et al., 2004; Hileman
et al., 2002); therefore, in states of hypertriglyceridemia such as obesity
or starvation, in which triglycerides are increasingly depended upon as
a source of energy, decreased leptin transport into the CNS is observed
(Banks et al., 2006). This reduced leptin transport has been proposed
as a mechanism whereby leptin resistance can develop in a state of
obesity (Banks et al., 2004) (Fig. 1). In the conventional sense, leptin
resistance implies an animal's inability to correctly modulate its energy
intake. Research has also demonstrated close cross-talk between insulin
and leptin cellular signaling pathways, particularly along the Jak2mediated PI3K and MAPK signaling cascades. Given this close relationship, resistance to the effects of both leptin and insulin occurs not only
in peripheral tissues but also in the CNS, initiating an adaptive increase
of obesogenic effects such as food intake and body weight gain through
intersection of the signaling pathways of the hormones (Clegg et al.,
2011; Konner et al., 2009; Myers et al., 2010).
The limited capacity of leptin transport from blood to brain represents a core principle of another recent theory of reduced functionality
of leptin signaling, centered on insufcient availability of leptin at leptin
receptors localized to the hypothalamus. The theory of central leptin insufciency postulates that, in response to high-fat diet (HFD)-induced

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C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

Fig. 1. Leptin signaling pathways and the mechanism and effects of leptin resistance. Multiple factors contribute to the accumulation of excess adipose tissue, including diet and nutrition,
genetic factors pertaining to metabolic activity and loci of fat deposition, and the process of aging. Adipocytes release the adipocytokine peptide hormone, leptin, into plasma circulation.
With normal circulating leptin levels, plasma leptin transport across the bloodbrain barrier (BBB) is facilitated by short-form leptin receptors in the cerebromicrovasculature. Leptin then
binds the long-form leptin receptor (Ob-Rb) to initiate intra-cellular leptin signaling. Binding the leptin receptor is essential to modulation of anti-apoptotic neuroprotective effects by
leptin. However, excess adipocyte deposition elevates circulating leptin, while unrestrained peripheral lipolysis and increased hepatic lipogenesis increase plasma triglyceride levels in
the obese state. It is theorized that in the hyperleptinemic state leptin resistance results from: 1) excess free triglyceride interference with transport of leptin across the BBB, and 2) blockade of distinct intracellular signaling pathways downstream of leptin. It is possible that leptin resistance results in attenuated leptin signaling, and attendant clinical pathology.

hyperleptinemia, increased pulsatile leptin secretion due to rhythmic

hormonal signaling downregulates cerebromicrovascular expression
of the short-form leptin receptor responsible for leptin transport across
the BBB (Hileman et al., 2002; Kalra, 2008; Kastin et al., 1999). This
theory also posits that independent leptin binding by C-reactive Protein
(CRP) and modulation of trans-BBB leptin transport by other metabolic
variables, such as alpha 1-adrenergic agents, in the peripheral circulation result in reduced leptin availability at long-form Ob-Rb leptin
receptor sites in the arcuate nucleus of the hypothalamus, attenuating
the leptin signaling cascade (Banks, 2001; Banks et al., 2004; K. Chen
et al., 2006; Kalra, 2008).
However, given the pleiotropic nature of leptin, other evidence
suggests that some downstream leptin-mediated functions, such as regulation of blood pressure (Rahmouni et al., 2005) and energy expenditure (Kaiyala et al., 2010), can be preserved even after the ability of
the hormone to regulate appetite has been blunted. Rahmouni et al.
found that diet-induced obesity in mice activated elevation of renal
sympathetic nervous activity (SNA) and blood pressure (BP) while
demonstrating resistance to the anorexigenic and weight-reducing
functions of leptin (Rahmouni et al., 2005), implying that leptin resistance is selective in the physiological responses that it blockades
(Correia et al., 2002; Mark, 2013; Mark et al., 2002; Rahmouni et al.,
2002). The selective leptin resistance was found to persist in dietinduced obese rats after administration of leptin by both intraperitoneal
and ICV routes. In light of these ndings, the theory of selective leptin
resistance synthesizes evidence that distinct leptin signal transduction
pathways exhibit pathway-specic modulation of cardiovascular and
metabolic function, and that a network of leptin receptors in the brain
exhibits site-specic leptin response and resistance (Mark, 2013).

Mechanisms of pro-survival and neuroprotective effects of leptin

In the periphery leptin has been found to exert a pro-survival
effect on a variety of cell types, including hepatic stellate cells
(Saxena et al., 2004), circulating monocytes (Najib and SnchezMargalet, 2002), and pancreatic -cells (Shimabukuro et al., 1998).
A pronounced pro-survival, anti-apoptotic effect of leptin has also
been observed in cells of the CNS. Russo et al. found that, compared
to non-exposed control cells of the same line, leptin-exposed neuroblastoma cells from the SH-SY5Y cell line had both a higher survival
rate as well as markedly downregulated gene expression of Caspase
10 and TNF-related apoptosis-inducing ligand (TRAIL), strong mediators
of cellular apoptosis (Russo et al., 2004).
This protective effect of leptin has been corroborated in both
in vitro and in vivo models of leptin rescue of neurons from neurotoxic insult. Leptin was found to blunt the pro-apoptotic effects of
6-hydroxydopamine (6-OHDA), a potent neurotoxin, on dopaminergic
cells in culture in a concentration-dependent manner, reducing levels
of mediators of cellular apoptosis such as cytosolic cytochrome c and activated cleaved caspase-3 and -9 (Weng et al., 2007). For cortical cells
exposed to N-methyl-D-aspartate (NMDA), an excitotoxin targeting
glutamate receptors, pre-treatment with leptin precipitated a dosedependent rescue from the toxic effects of NMDA on cortical cell viability (Dicou et al., 2001). Furthermore, studies by Guo et al. demonstrated
that hippocampal neurons treated with leptin had signicantly higher
rates of survival under each of the three following conditions compared
to saline-treated cells: exposure to excitotoxic glutamate; exposure to
Fe2+, an oxidative agent; and withdrawal of neurotrophic factors
(Guo et al., 2008; Russo et al., 2004). Leptin-treated neurons were

C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

shown to have more stable mitochondrial membranes, attenuated

production of mitochondrial reactive oxygen species, and elevated production of the anti-apoptotic protein Bcl-xL as compared to control
cells. Thus, exogenous leptin administration can rescue neuronal cells
from potential damage induced by toxic insult, oxidative stress, or
pro-apoptotic signaling in cell models.
In mice, leptin or saline pretreatment followed by injection with
6-OHDA was found to result in signicant preservation of dopaminergic
neurons in the Substantia Nigra Compacta (SNc) in the leptinpretreated group as compared to saline pretreatment up to two months
after 6-OHDA exposure (Weng et al., 2007). Similarly, leptin attenuated
6-OHDA-induced turning preference in the mice, suggesting that leptin
not only protects at a cellular level but also maintains function lost due
to neurotoxin exposure. Another study (Dicou et al., 2001) showed that,
while intracerebral injections of ibotenate, a glutamate analog, resulted
in dramatic loss of mouse cortical neurons, co-administration of leptin
with ibotenate lessened the extent of neuronal loss in a dose-dependent
fashion. Intraperitoneal injection of leptin directly after the intracerebral injection of ibotenate yielded the same result as when the two
compounds were co-administered intracerebrally, suggesting that
peripheral leptin exerts a neuroprotective effect equal to that of direct
leptin delivery to the CNS.
The signicant evidence in support of leptin as a neuroprotective
agent has stimulated further investigation into the specic signaling
and molecular pathways modulated by the adipokine. As previously
discussed, leptin activates signaling systems that include Jak2/STAT 3,
MEK/ERK, PI3K/Akt, STAT 5, and SHP-2/SOCS3 pathways (C. Chen
et al., 2006; Frhbeck, 2006; Guo et al., 2008) (Fig. 2). The ability of

65

leptin to stimulate these pathways lends a signicant survival advantage to cells exposed to leptin within a pro-apoptotic environment.
The Jak2 signaling pathway was among the rst to be shown experimentally to modulate the downstream pro-survival signal of leptin. In
cell cultures of mouse cortical cells, AG490, an inhibitor of Jak2, was
added to a solution of leptin and NMDA to assess for cell survival compared to cells exposed to only NMDA and leptin (Dicou et al., 2001).
Signicantly fewer cells survived in the group of cells exposed to
AG490. The group also investigated this phenomenon in vivo by injecting
a combination of ibotenate, leptin, and AG490 intracerebrally. When leptin was co-administered with ibotenate and the Jak2 inhibitor, all of the
neuroprotective effects of leptin were reversed. The Jak2 inhibitor
also fully reversed the anti-apoptotic role of leptin in hippocampal
neurons exposed to oxidative Fe 2+, glutamate, or an environment
lacking neurotrophic factors (Guo et al., 2008; Russo et al., 2004).
Furthermore, Jak2 inhibition reduced the leptin-induced rise in manganese superoxide dismutase (Mn-SOD) and B-cell lymphoma-extra
large (Bcl-XL) protein, both key elements in blocking apoptosis.
To further elucidate the anti-apoptotic mechanism of leptin, Russo,
et al. used a series of inhibitors of major signal transducers Jak2 inhibitor, PI3K inhibitor, p38MAPK inhibitor, and two different MEK inhibitors on neuroblastoma cells in vitro (Russo et al., 2004). After treating
all of the cells with leptin, they observed that serum-free neuroblastoma
cells were more vulnerable to apoptosis when in the presence of Jak2
inhibitor, PI3K inhibitor, or one of the two inhibitors of MEK, as measured by DNA fragmentation. However, the anti-apoptotic effects of
leptin were preserved after exposure to p38MAPK inhibitor or the
second MEK inhibitor. Decreased caspase-3 activity in the neuroblastoma

Fig. 2. Intra-cellular signaling pathways of leptin and their possible implications for Alzheimer's and Parkinson's diseases. Upon leptin binding and dimerization of the leptin
receptor (Ob-Rb), the intra-cellular, Ob-Rb-associated Jak2 tyrosine kinase is activated, which phosphorylates Ob-Rb tyrosine residues that recruit and activate several key transcription
factors and kinases, including signal transducer and activator of transcription (STAT) 3 and phosphoinositide-3-kinase (PI3K). In Alzheimer's disease conditions leptin modulates the
STAT3/AMPK pathway to inhibit the production of amyloid precursor protein (APP) secretase, mediating decreased production of beta-amyloid plaque. Meanwhile, the leptinmediated PI3K/AKT pathway inhibits downstream production of tau protein, which amasses to produce neurobrillary tangles (NFTs) in the pathologic Alzheimer's disease state. In
the context of Parkinson's disease, leptin modulates the phosphorylation of Ob-Rb tyrosine residues that activate mitogen-activated protein kinase (MAPK). MAPK then activates
cAMP response element-binding (CREB) protein, which has an anti-apoptotic effect on the cell. It is possible that leptin could mediate neuroprotective effects on dopaminergic cells
via the MAPK/CREB pathway in pathologic Parkinson's disease.

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C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

cells upon inhibition of Jak2, MEK/ERK and PI3K pathways indicated the
importance of these pathways as mediators of leptin-induced neuroblastoma cell survival.
The role of the PI3K/Akt pathway in transduction of the leptinmediated survival signal was further conrmed in a study in which neuroblastoma cells were pretreated with 1-methyl-4-pyridinium (MPP+),
a neurotoxin that targets dopamine-producing neurons (Lu et al., 2006).
When the leptin-pretreated SH-SY5Y cells were exposed to both leptin
and PI3K inhibitor, it was found that PI3K inhibitor signicantly
inhibited leptin-associated neuroprotection against MPP+. Interestingly, this reversal of leptin-mediated neuroprotection was not observed
when cells were exposed to Jak2 inhibitor or MEK inhibitor. The
authors hypothesized that in neuroblastoma cells exposed to MPP+,
leptin-mediated neuroprotection involved a Jak2-independent pathway. Further studies on hippocampal cells conrmed that PI3K inhibitor
reduced the ability of leptin to protect these cells against glutamate
toxicity (Guo et al., 2008; Russo et al., 2004).
Following Russo's investigation into several of the major signaling
pathways implicated in leptin-induced neuroprotection, the importance of the MEK/ERK signaling pathway was conrmed when the pathway was found to activate and promote nuclear localization of cAMP
response element-binding protein (CREB), a known prosurvival transcription factor in dopaminergic cells (Weng et al., 2007). Inhibitors of
the MEK pathway were found to reverse the neuroprotective effects of
leptin administration by reduction of phosphorylation and activation
of ERK 1,2 and CREB, thus preventing the propagation of leptin signaling. Similarly, for neurons genetically modied by knocking out the
Jak2 gene or transfected with decoy DNA to prevent activation of
CREB, both neuron types lost the survival advantage of leptin upon
challenge with 6-OHDA.
Leptin action in animal models of neurodegenerative disease
Since the above evidence suggests that leptin confers a pro-survival
signal to neurons by interfering with the apoptotic cascade induced by
harsh environments, it is of considerable clinical relevance to examine
the role leptin plays in models of neurodegenerative disease. To what
extent can leptin salvage cells affected by the pathophysiological
processes of diseases such as Alzheimer's disease (AD) and Parkinson's
disease (PD)? If it can be shown to salvage these cells, what is the functional outcome of leptin treatment on such disease states?
Alzheimer's disease
Alzheimer's disease is characterized by pathologic buildup of two
neurotoxic substances: extracellular amyloid plaque, as a result of an
excess deposition of -amyloid (A); and intracellular neurobrillary
tangles (NFT), a consequence of hyperphosphorylation of tau protein
(Ittner and Gotz, 2011). Tau is a microtubule-associated protein localized largely in the axons of neuronal cells that promotes the binding
of microtubules and polymerization of tubulin to build crossbridges
between microtubules and to elongate the axon body (Harada et al.,
1994). Tau protein is regulated by various kinases, most notably by Protein Kinase N (PKN), which specically phosphorylates tau to promote
microtubule disarray responsible for NFT formation (Taniguchi et al.,
2001). In light of the common belief that the abnormal deposition of
both amyloid and NFT are central to the pathogenesis of AD, it has
been demonstrated that leptin plays a role in reversing both pathological hallmarks of AD and results in better neurological outcomes for the
disease state (Fewlass et al., 2004; Greco et al., 2009, 2010).
Modulation of tau protein phosphorylation by leptin represents a
signicant pathway for protection against Alzheimer's disease pathology.
Greco et al. found that, in cell cultures of Human neuroblastoma, SHSY5Y, leptin resulted in time- and concentration-dependent decreases
in phosphorylation at Ser396 of tau, which in turn affected the binding
of tau to microtubules in the cell. Further experimentation showed

similar results for other known sites of tau phosphorylation at Ser202

and Ser404 in AD. This observation indicates that leptin can affect phosphorylation of multiple sites on the tau protein that are thought to contribute to AD pathology. The investigators then explored the effects of
AMP-activated protein kinase (AMPK) signaling on leptin actions on
tau. They found AMPK activation in response to leptin; however, with
joint administration of leptin and compound C, an inhibitor of AMPK,
they observed a blunting of tau dephosphorylation. Furthermore, addition of the AMPK activator AICI ribonucleotide (AICAR) was sufcient
to produce a decrease in phosphorylation of Ser396 of tau protein. These
ndings strongly suggest that leptin is responsible for a decrease in phosphorylated tau via the AMPK signaling pathway.
In examining other key signal transduction modulators, it was determined that inhibitors of AMPK and p38 MAP kinase were successful in
diminishing leptin-mediated dephosphorylation of Ser396 of tau protein
(Greco et al., 2009). Fewlass et al. investigated leptin action on amyloid
plaques in the CNS (Fewlass et al., 2004). They found that leptin incubation resulted in dose- and time-dependent decreases in -amyloid
plaque (A) extracted from culture media by the inhibition of
-secretase (BACE), an enzyme responsible for cleavage of the amyloid
precursor protein necessary in the formation of A. Greco et al. also investigated the role that downstream AMPK signal transduction played
in the capacity of leptin to decrease A production (Greco et al.,
2009). They found that leptin-treated or AICAR-treated neuroblastoma
cells have signicantly less -amyloid plaque (A) and that addition of
compound C, an AMPK inhibitor, or an inhibitor of peroxisome
proliferator-activator receptor- (PPAR) reversed the neuroprotective
effects of leptin. PPAR is a nuclear receptor activated by AMPK that
functions to inhibit transcription of BACE, and thus helps to prevent
A deposition (Wang et al., 2013). The investigators also found that
AKT inhibition, an important component of regulation of the tau phosphorylation via upstream AMPK, failed to signicantly decrease A
levels, leading them to hypothesize that AMPK is the last common signaling molecule in the pathway by which leptin modulates downstream levels of neurobrillary tangle and -amyloid plaque (Greco
et al., 2009). They proposed that following AMPK activation, two separate signaling pathways diverge: one pathway involving activation of
PPAR and BACE for A regulation, and another pathway for downregulation of tau phosphorylation involving AKT and glycogen synthase
kinase-3 (GSK-3).
Recent studies suggest that Alzheimer's disease pathologies could
progress as a result of the development of leptin resistance localized
to specic regions of the brain (Bonda et al., 2014). Bonda et al. found
that subjects with AD had higher CSF leptin levels as compared to age
and BMI-matched controls, and that, at the time of autopsy, subjects
with the highest CSF leptin levels had the worst AD pathology noted.
Furthermore, they discovered that, in spite of increased co-localization
of NFT and Ob-Rb expression in AD patients, the concentration of activated leptin receptors was lower in the hippocampus containing NFT
as compared to neurons lacking NFT. These ndings led the authors to
speculate that neurons with NFT lose the ability of leptin to transmit
its pro-survival message in the most vulnerable neuronal population
perpetuating the disease state.
In 2010, Greco et al. investigated whether leptin treatment reduces
the burden of A and NFT in the CRND8 transgenic mouse model,
which encodes a mutant form of the amyloid precursor protein and
has been established as a model for familial, early onset Alzheimer's
disease (Greco et al., 2010). The investigators also studied the cognitive
performance of the mice at four and eight weeks after leptin treatment.
Leptin-treated mice had signicantly lower extractable levels of brain
and serum A compared to vehicle-treated mice. Similarly, immunohistochemistry revealed an approximately 50% reduction in A deposition
in the hippocampus. In accordance with previous in vitro studies, the
group found that leptin-treated mice had signicantly less phosphorylated tau protein as compared to control mice at several different brain
locations. The leptin-treated transgenic mice signicantly outperformed

C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

the saline-treated controls in both novel objection recognition and fear

conditioning, demonstrating that leptin treatment not only reduced
pathological evidence of AD, but also resulted in functional improvement in cognitive performance.
Parkinson's disease
As presented earlier, leptin has been found to promote the survival
of neuroblastoma and neural dopaminergic cells in the presence of
6-OHDA and MPP+, dopamine cell-specic neurotoxins commonly
used in models of PD (Ho et al., 2010; Lu et al., 2006; Weng et al.,
2007). Leptin was shown to protect the neuroblastoma cells via a PI3K/
Akt-dependent pathway (Weng et al., 2007). Akt inhibition, an important
component of the signaling cascade implicated in regulation of the tau
phosphorylation via upstream AMPK, failed to signicantly decrease A
levels. Meanwhile, a MEK/ERK1,2-induced rise in CREB activation preserved dopaminergic cell survival in pro-apoptotic conditions (Weng
et al., 2007). In vivo experimentation revealed that, up to two months
after neurotoxin exposure, motor behavior is salvaged in leptin-treated
animals compared to controls in dopaminergic-destructive environments in part through preservation of nigrostriatal functionality. Furthermore, leptin treatment increased the expression in neuroblastoma cells
of mitochondrial Uncoupling Protein-2 (UCP2) and Uncoupling Protein4 (UCP4), both vital to the reduction of oxidative stress in mitochondria
(Ho et al., 2010). UCP2 knockdown cells were shown to lose the protective effects of leptin when challenged with MPP+.
As described above, CREB appears to be a key factor in leptininduced neuron survival, while UCP2 is a known gene target for CREB
(Lonze and Ginty, 2002). Although not yet tested formally, drawing a
link between leptin-induced CREB activation and UCP2 upregulation
in the context of survival advantage to stressed cells would seem to be
supported by the literature. The same study by Weng et al. in 2007
reported brain-derived neurotrophic factor (BDNF) to be another
downstream product of leptin mediated by MEK/ERK/CREB activation
(Weng et al., 2007). As is the case for leptin, exogenous BDNF alone
can rescue dopaminergic neurons from 6-OHDA exposure (Spina et al.,
1992), potentially via a CREB-dependent pathway. BDNF is known to
signal through similar PI3K-Akt and MEK-ERK channels as leptin, with
the MEK-ERK pathway implicated in BDNF expression via CREB mediation. In this sense, leptin-induced BDNF release would appear to play a
positive feedback role in cell survival (Signore et al., 2008).
Leptin, obesity and neurodegeneration
Obesity especially central obesity is related to a variety of neurodegenerative conditions, as well as altered brain morphology and cognitive ability (Fitzpatrick et al., 2009; Gustafson et al., 2009; Lee, 2011). As
both rates of obesity and dementia continue to rise in the American
population, it will be important to further characterize the relationship
between the two conditions. Obesity is a complex condition with an
array of metabolic derangements, including insulin resistance, dyslipidemia, cardiovascular events and diabetes mellitus, all of which likely
play a role in the pathophysiology of dementia (Dixon, 2010). An important aspect of obesity that should not be overlooked in this discussion is
leptin resistance. While obesity represents a state of hyperleptinemia,
leptin in the obese individual does not work effectively on the hypothalamus to regulate energy intake and expenditure, analogous to the aforementioned animal models of leptin resistance (Enriori et al., 2006).
There are two observations regarding the mechanism of development
of leptin resistance. The rst is decreased leptin uptake into the CNS
(Banks and Farrell, 2003), due at least in part to high triglyceride levels
(Banks et al., 2004) and downregulation of cerebromicrovascular leptin
transporter receptors (Hileman et al., 2002; Kastin et al., 1999). The
second is attenuated intracellular leptin signaling. Potential mechanisms for leptin signal blunting include increased expression of suppressor of cytokine signaling 3 (SOCS3) protein and the protein

67

tyrosine phosphatase PTP1B, as observed in states of leptin elevation

(Munzberg and Myers, 2005). Upon leptin binding of the Ob-Rb receptor, activation of STAT3 protein bound to tyrosine residues on the ObRb intracellular domain promotes SOCS3 activation (Banks et al.,
2000). SOCS3 then binds to STAT3, the Ob-Rb-associated Jak2 protein,
and tyrosine residues on Ob-Rb to mediate inhibition at all of these
sites, effectively blunting downstream effects of leptin. PTP1B, a tyrosine
phosphotase expressed in leptin-sensitive neurons of the hypothalamus, has also been found to mediate an inhibitory effect on leptin signaling in vivo by direct, selective dephosphorylation of the STAT3 and Jak2
signaling molecules (Lund et al., 2005).
Similarly blunted signal transduction is also observed with aging. It
has been shown that older rats have less STAT3 activation and fewer
leptin receptors as compared to younger rats (Fernandez-Galaz et al.,
2001; Scarpace et al., 2000). In addition, expression of PTP1B and
SOCS3 is increased in hypothalamic neurons of old rats as compared
to young rats (Morrison et al., 2007; Peralta et al., 2002). It is possible
that the increased leptin resistance seen with age is related to the
increase in fat mass that occurs with aging. As an individual ages, fat
mass increases in the body overall, particularly favoring central adiposity (RS S., 1998). With the onset of obesity and attendant systemic insulin resistance (Rotter et al., 2003), the inhibitory effect of insulin on
lipolysis is attenuated. Unrestrained lipolysis as a result of blunted insulin inhibition and paracrine activation by obesity-associated inammatory cytokines results in elevated levels of circulating free fatty acids
(Greenberg et al., 2001). Furthermore, as increased adiposity leads to
a concurrent hyperleptinemic state, both insulin resistance and
hyperleptinemia potentially contribute to leptin resistance. However,
increased leptin levels (an indirect measurement of leptin resistance)
were found in aged rats independent of increasing adiposity (Li et al.,
1997). It has yet to be determined whether other factors connect increased age to the development of leptin resistance. Age is also a strong
risk factor for dementia. As both increased age and obesity are associated with states of leptin resistance, it will be important to examine the
relationships among obesity, age and neurodegenerative conditions to
determine whether leptin resistance may reveal a pathophysiological
link among these conditions.
Both age and obesity are associated with worse outcomes after
neurodestructive events such as Traumatic Brain Injury (TBI), ischemia
and neurotoxin challenge. Older age is a strong predictor of poorer functional outcomes after a TBI (Jacobs et al., 2010; Katz and Alexander,
1994; Mosenthal et al., 2004). The relationship of obesity to TBI outcome
is more controversial. Some studies have found that obesity is an independent predictor for mortality following blunt trauma (Neville et al.,
2004). However, more recent studies have been unable to identify obesity as a risk factor for worse outcomes in patients following TBI (Brown
et al., 2006). It is hypothesized that the higher mortality rate in some
study groups is due to a higher incidence of complication in the obese
population following brain injury compared to lean controls.
However, it is difcult to establish causal relationships between obesity, leptin resistance, and stroke incidence, given that the contribution
of obesity-induced metabolic and cardiovascular changes to stroke likely overshadow any association between stroke and leptin resistance
alone. It has been established that leptin treatment attenuates cerebral
ischemia and reperfusion injury (Zhang et al., 2007, 2011, 2013). In
fact, obese ob/ob mice exhibited greater infarct area after occlusion
and reperfusion of the middle cerebral artery compared to lean controls
(Terao et al., 2008). Infarct size in the ob/ob mice replete with leptin in
the acute setting was similar to that of the ob/ob mice with normal
leptin levels, rather than to the lean mice with normal leptin. Given
the hyperlipidemia found in ob/ob mice, this nding likely supports
the concept of obesity-induced leptin resistance at the BBB, rather
than discounting the role of leptin in the attenuation of ischemic
damage. It has been hypothesized that part of the reason for the
exaggerated response to ischemic stroke is related to the higher level
of inammation in the obese versus lean mice.

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C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

Obese human subjects were found via positive emission tomography

(PET) scans to have fewer dopaminergic receptors in the nigrostriatum
than did lean controls (Wang et al., 2001). Obese ob/ob leptin-decient
mice had higher mortality rates and neuronal damage due to methamphetamine and kainic acid neurotoxicity compared to lean controls
(Sriram et al., 2002). Moreover, Choi et al. found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that destroys the
dopaminergic neurons in the substantia nigra leading to Parkinsonism,
was far more detrimental in overfed, obese mice than in their lean counterparts (Choi et al., 2005). Similarly, Morris et al. found that rodents
with diet-induced obesity had greater depletion of dopaminergic neurons after 6-OHDA infusion (Morris et al., 2010). Of particular relevance
to Parkinson's disease, these experiments suggest that, in states of
obesity and accompanying leptin resistance, it is likely that innate neuroprotection is lost due to decreased leptin functionality.
Disordered leptin signaling in the hypothalamus is thought to be a
common pathway connecting obesity not only to neurodegeneration,
but also to metabolic disorder, which leptin mediates through the regulation of appetite and energy balance (Myers et al., 2008; Wurtman,
1996). Because of this functionality, leptin has attracted much attention
as a potential therapeutic tool for use in patients with obesity and
metabolic disorders. Leptin-decient human subjects treated with
leptin replacement therapy have demonstrated sustained weight loss
attributable to reduced energy intake and appetite over a twelvemonth period, further evidence of the role of leptin signaling in obesity
etiology (Farooqi et al., 1999) Furthermore, leptin-hypothalamic signaling also modulates the fat accrual network (FAN). The FAN, a distinct
circuit of neural efferents from the hypothalamus to the pancreas,
skeletal muscles, and white and brown adipose tissue depots, interacts
with the energy and appetite regulatory networks also mediated by the
hypothalamus to stimulate central and peripheral glucose metabolism
and to suppress pancreatic insulin secretion (Kalra and Kalra, 2010;
Kreier et al., 2006; Uyama et al., 2004). Various studies have shown
that interference with descending neural pathways from leptin action
sites in the hypothalamus results in hyperglycemia, hyperinsulinemia,
obesity, diabetes, and dyslipidemia (Kalra and Kalra, 2010; Kalra et al.,
1999). Furthermore, the use of recombinant, adenovirus-associated
leptin gene therapy injections at both intramuscular and intracerebroventricular sites in type 1 diabetic transgenic mouse models restored
and sustained euglycemia in these mice, likely via increased glucose
metabolism and disposal, energy expenditure, and leptin FAN signaling
due to increase in endogenous leptin production in the hypothalamus
(Petersen et al., 2002; Ueno et al., 2006).
The ameliorative effects of leptin extend to some other metabolic
disorders as well. In both lipodystrophic mice and congenitally
lipoatrophic humans with severe leptinopenia and resultant hyperglycemia and insulin insensitivity, leptin replacement therapy was
shown to successfully restore euglycemia and insulin sensitivity
(Ebihara et al., 2007; McKnight, 1998). Further studies conrmed that
in generalized lipodystrophy, a disease of pathological deciency in
adipose tissue, leptin therapy both reduced patient caloric intake and
decreased storage of excessive fat in nonadipose tissue such as the liver,
attended by decreased hepatic steatosis, hypertriglyceridemia, and resultant insulin resistance (Oral et al., 2002; Savage and O'Rahilly, 2002).
Clinical applications for leptin
A signicant body of research now indicates that leptin promotes
cell survival via suppression of apoptosis. This protection is observed
at both physiologic and pharmacologic doses. Epidemiologic studies
are less conclusive but do suggest that leptin resistance exacerbates progression of neurodegeneration (Lieb et al., 2009; Zeki Al Hazzouri et al.,
2012). Investigation of the possible clinical applications garnered from
the above research is underway. For one, there appears to be a role for
weight loss and calorie restriction in preventing the progression of
Alzheimer's disease in animal models (Patel et al., 2005). Patel et al.

found that both amyloid plaques (size and number) as well as astrocyte
activation were decreased in calorie-restricted animals compared with
those with unlimited access to food. Clinical trials are currently underway to examine the inuence of caloric restriction on cognitive performance and slowing of cognitive decline in human patients above age 60
with mild cognitive impairment, with the hypothesis that caloric
restriction and lifestyle counseling would result in weight loss, reduction
of circulating leptin levels, decreased risk of dementia, and improvement
or reduction in the rate of decline in cognitive performance (Hospital
UoSPG, 2011). A meta-analysis performed on many studies of earlyphase Alzheimer's human patients supports the role of nutritional modication in prolonging life and expands on the role of caloric restriction in
animal models (Burgener et al., 2008).
An interest in using leptin to directly treat neurodegenerative disorders has been the focus of increasing attention. Matochik et al. demonstrated that 18 months of leptin replacement therapy at physiological
doses for patients with congenital leptin deciency resulted in signicant increases in gray matter volume in the anterior cingulated gyrus,
the inferior parietal lobule and the cerebellum but not in the hypothalamus and that this increased volume persisted over the next period of
18 months, reversing after an interval of withdrawal of leptin therapy
(Matochik et al., 2005; Paz-Filho et al., 2010). The clinical benet of leptin replacement therapy has important consequences for patients with
Alzheimer's disease, who have been found to have signicantly lowered
serum leptin levels (Power et al., 2001). Holden et al. prospectively
studied 2871 elderly subjects over a span of four years to nd that subjects with low serum leptin levels were more likely to develop AD than
patients with high leptin levels (Holden et al., 2009). Further studies
have demonstrated the correlation between low plasma levels of leptin
and early AD onset (Bigalke et al., 2011), while a study of 785 healthy
patients from the Framingham cohort over the course of 8.3 years revealed an association between elevated leptin levels and both increased
cerebral volume and decreased risk of dementia, noting a fourfold increase in risk of AD from the lowest to highest quartile of leptin levels
among the participants (Lieb et al., 2009). Of note, the neuroprotective
effects of high levels of leptin were observed among lean patients but
not among obese patients, likely because of leptin resistance among
the obese. Collectively, these ndings suggest exogenous leptin replacement therapy as a potential treatment method for leptin-decient
patients either before or after onset of neurodegenerative diseases
such as Alzheimer's and Parkinson's.
Another future potential therapeutic avenue for leptin involves the
use of viral vector-associated leptin gene therapy to deliver leptin to
specic receptor sites in the brain. Recently, Perez-Gonzalez et al.
found that leptin delivery via lentiviral vector into transgenic APP/PS1
mice, a rodent model that exhibits AD-like alterations due to overexpression of APP and PS1 proteins, reduced pathological A accumulation and improved synaptic density and neurite length in cortical
and hippocampal regions three months after vector delivery (PerezGonzalez et al., 2014). Elevation of endogenous brain expression of
leptin by leptin gene therapy has also been shown to restore euglycemia
in mouse models of type 1 diabetes (Ueno et al., 2006) and to improve
insulin sensitivity in type 2 diabetic models (Boghossian et al., 2006,
2007). While gene therapy with diverse viral vectors has been tested
frequently in clinical trials for its efcacy against both Alzheimer's and
Parkinson's diseases (Kaplitt et al., 2007; Marks et al., 2008, 2010), conclusive clinical trials of leptin application in gene therapy have yet to be
executed.
In spite of these promising ndings, it does not appear that any clinical trials are currently underway to directly test the impact of leptin
therapy on neurodegenerative disease by central or peripheral routes.
In the event that clinical trials of therapeutic leptin are undertaken,
they should take into account the obesity-induced leptin resistance at
both the cererobromicrovascular and signaling transduction level that
has been found to associate with neurodegenerative diseases such as
Alzheimer's disease (Bonda et al., 2014). Roth et al. in 2008 reported

C. Davis et al. / Neurobiology of Disease 72 (2014) 6171

that peripheral co-administration of leptin and the pancreatic peptide

hormone amylin resulted in restored leptin responsiveness, signicant
weight loss, and reduced food intake in rats with diet-induced obesity
and leptin resistance (Roth et al., 2008). Leptin-resistant rats treated
with the leptinamylin synergy experienced weight loss dissociable
from their reduced food intake that coincided with restored leptin signaling in the ventromedial hypothalamus and area postrema. This
same leptinamylin combination therapy has been found to yield significant clinical benet for patients with lipodystrophy resulting in
sizeable reductions in hemoglobin A1C, triglyceride, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (Chan
et al., 2011) but has yet to be tested on humans for its effect on leptin
resistance or neurodegenerative disease. Current clinical trials of leptin
amylin combination therapy seek to investigate the impact of the treatment method on reduction of obesity via leptin signaling pathways
(Pharmaceuticals B-MSA, 2008b), or to investigate the use of leptin
alone on diabetes or hypertriglyceridemia associated with lipodystrophy
(Pharmaceuticals B-MSA, 2008a). However, evidence from studies in
animal models suggests that further exploration of the ameliorative effect
of combined leptinamylin treatment on leptin resistance could facilitate
the use of leptin as a neuroprotective agent in both leptin-sensitive nonobese and leptin-resistant obese patients. This research would have
potential to yield novel pharmacologic treatment and prophylactic
options for neurodegenerative disease in a large patient population.
Conclusions
Beyond its role in satiety and energy balance, leptin has been found
to be a major factor in reproductive function, bone metabolism, sympathetic nerve activity, and neuroplasticity. Basic science ndings suggest
that leptin can reduce or prevent neuronal apoptosis induced by a
variety of pathological conditions and could result in better functional
outcomes for neurodegenerative disease states, especially those associated with obesity and metabolic disorders. Given the strong association
among obesity, metabolic disorders and neurodegeneration, and in light
of the rapid increase in prevalence of obesity and attendant leptin resistance, future clinical trials could explore means of overcoming leptin
resistance in order to reduce obesity, associated metabolic dysfunction,
and likelihood of onset of neurodegenerative disease later in life. In
spite of recent discoveries delineating the mode of action of leptin, what
remains to be seen is how the disease-modifying effects of the hormone
in pre-clinical trials will translate to effective treatment options for patients amid the advancing epidemics of obesity and neurodegenerative
disease.
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