Review
Role of hypothalamic neurogenesis in
feeding regulation
Lı́gia Sousa-Ferreira1, Luı́s Pereira de Almeida1,2, and Cláudia Cavadas1,2
1
Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517 Coimbra, Portugal
2
Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
The recently described generation of new neurons in the
adult hypothalamus, the center for energy regulation,
suggests that hypothalamic neurogenesis is a crucial part
of the mechanisms that regulate food intake. Accordingly,
neurogenesis in both the adult and embryonic hypothal-
amus is affected by nutritional cues and metabolic dis-
orders such as obesity, with consequent effects on
energy-balance. This review critically discusses recent
findings on the contribution of adult hypothalamic neu-
rogenesis to feeding regulation, the impact of energy-
balance disorders on adult hypothalamic neurogenesis,
and the influence of embryonic hypothalamic neurogen-
esis upon feeding regulation in the adult. Understanding
how hypothalamic neurogenesis contributes to food
intake control will change the paradigm on how we
perceive energy-balance regulation.
Neurogenesis in the adult brain
Neurogenesis is a complex and highly regulated process
that results in the production of new neurons (see
Glossary). Neurogenesis occurs at high rates during the
embryonic period when substantial quantities of new cells
are generated by the proliferation of neuroprogenitor cells
(NPCs), and subsequently migrate to the developing tis-
sue [1]. In the adult, neurogenesis occurs at low rates in
discrete regions of the brain such as the subventricular
zone (SVZ) of the lateral ventricles and the subgranular
zone (SGZ) of the hippocampus [2]. NPCs from these
regions proliferate and migrate to their final destination,
the olfactory bulb and the granule cell layer of the dentate
gyrus, respectively, where they differentiate to form new
neurons and integrate into pre-existing circuits [3]. Im-
portantly, neurogenesis is not simply a restorative mech-
anism; it represents a functional response of the organism
to daily challenges imposed by environmental and inter-
nal states [2]. Moreover, the new neurons produced
through the adult life seem to contribute to behavioral
functions such as learning, memory consolidation, and
mood regulation [3].
Corresponding author: Cavadas, C. (ccavadas@uc.pt).
Keywords: hypothalamus; neurogenesis; neural stem cells; food intake; obesity;
neuropeptide Y; proopiomelanocortin.
1043-2760/$ – see front matter
ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2013.10.005
80 Trends in Endocrinology and Metabolism, February 2014, Vol. 25, No. 2
A new neural stem/progenitor cell niche has recently
been described to reside in the adult hypothalamus, a
brain region that functions as the central regulator of
homeostasis by controlling food intake, metabolism, and
Glossary
Arcuate nucleus (ARC): a region of the hypothalamus where the nutrient-
sensing neurons are located.
Ependymal cells: cubic ciliated cells that line the ventricles (cavities) of the brain.
In addition to barrier functions, ependymal cells are involved in the production
and circulation of the CSF. In the hypothalamus, ependymal cells are the interface
between the third ventricle (3V) and hypothalamus parenchyma.
Feeding regulation: a complex mechanism that includes central processes that
take place in the hypothalamus. In brief, ARC neurons receive peripheral signals
regarding the energy status of the organism and synthesize neuropeptides in
response to those signals. The neuropeptides help in integrating and translating
those signals into motivated behavior. Usually, hypothalamic responses
counteract the nutritional signals to re-establish energy homeostasis.
Growth factors: molecules that increase the generation and/or survival of
progenitor neuronal cells in neurogenic areas of the adult brain.
Hypothalamus: a brain area responsible for feeding regulation and
metabolism. It consists of several regions (nuclei) with different neuronal
populations that express specific neuropeptides. The hypothalamus is located
in close proximity to the 3V.
Hypothalamic neurogenesis: the generation of new neurons in the adult or
embryonic hypothalamus that arise from the proliferation and differentiation of
hypothalamic NPCs.
Leptin: an anorexigenic hormone released from adipocytes into the circulation
as a function of body fat content. High levels of fat storage raise the
concentrations of leptin, and leptin suppresses food intake by inhibiting
NPY/AgRP neurons and activating POMC neurons.
Neurogenesis: the set of events leading to the production of new neurons from
NPCs. This process includes division (proliferation) of NPCs, migration,
maturation (differentiation to a specific neuronal type), and functional
integration of the new neurons into existing neuronal circuits.
Neurogenic niche: the zone(s) in the adult brain where NPCs are retained after
embryonic development. The microenvironment in the neurogenic niche,
including cell–cell interactions, can retain the NPCs in the undifferentiated state
and regulate the proliferation and differentiation of NPCs [66].
Neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons: a group of
neurons located in the ARC that express NPY and AgRP; these neuropeptides
have orexigenic actions (increase food intake) and are activated during energy
deficiency.
Neuroprogenitor cells (NPC): the population of cells with proliferative and self-
renewal capacity that can differentiate to different neural phenotypes.
Paraventricular nucleus (PVN): region of the hypothalamus that receives most
of the neuronal projections from the ARC neurons.
Proopiomelanocortin (POMC) neurons: a group of neurons located in the ARC
that express POMC; neuropeptides resulting from processing and cleavage of
the POMC gene product have anorexigenic actions (decrease food intake) and
are increased in situations of energy excess.
Subependymal astrocytes: glial cells located beneath the ependymal layer of
the 3V wall that present features of neural stem cells, including expression of glial
fibrillary acidic protein (GFAP) and proliferation upon growth factor stimulation.
Therefore, subependymal astrocytes are identified as adult hypothalamic NPCs.
Tanycytes: specialized non-ciliated ependymal cells characterized by a long
basal process that penetrates into the hypothalamic parenchyma. Tanycytes
are considered to be adult hypothalamic NPCs because they are proliferative in
basal conditions and upon stimulation with growth factors, and express the
neuroprogenitor markers vimentin and nestin.
Review
body temperature, among other functions. Emerging evi-
dence discussed in detail below suggests that these adult-
born hypothalamic neurons play a crucial role in feeding
regulation, underscoring their significance in the central
control of energy-balance.
Hypothalamus and feeding regulation
Feeding behavior and energy-balance are regulated cen-
trally by the hypothalamus. Distinct nuclei within the
hypothalamus, including the arcuate nucleus (ARC), the
paraventricular nucleus (PVN), the ventromedial (VMH)
and dorsomedial (DMH) hypothalamus, and the lateral
hypothalamic area, share neuronal interconnections
and together they maintain body homeostasis [4]. ARC
neurons produce the orexigenic neuropeptides neuropep-
tide Y (NPY) and agouti-related protein (AgRP) that act to
increase food intake, and the anorexigenic neuropeptide
proopiomelanocortin (POMC), the product of which (a-
MSH) acts to decrease food intake [5]. The activity of
ARC neurons is regulated by metabolic peripheral signals
including hormones and gastrointestinal peptides [4]. For
example, the adipose-derived hormone leptin, which is
produced in proportion to body fat content, can activate
the leptin receptors present in ARC neurons [4] to increase
the expression and release of POMC and reduce the ex-
pression and release of NPY, resulting in a decrease in food
intake [5]. More recently, neurogenesis has been described
in the hypothalamus and has been shown to participate in
the response of hypothalamic neuronal circuits to meta-
bolic signals [6–9].
Embryonic hypothalamic neurogenesis influences adult
feeding regulation
Cell populations during embryonic hypothalamic
neurogenesis
The development of hypothalamic feeding circuits starts
during the embryonic period and, in rodents, continues
through the first 2 weeks of postnatal life [10]. Recent
studies show that hypothalamic NPCs are present in the
embryonic hypothalamus; for example, in rodents, POMC
and NPY neuroprecursors are identified as early as em-
bryonic (E) days E10.5 and E14.5, respectively [11,12]. In
agreement, NPCs isolated from fetal rat hypothalamus
express neuropeptides NPY, AgRP, and POMC [13]. Im-
portantly, the number of immature POMC neurons in the
ARC triples and reaches its adult number during the fetal
period [11]. Surprisingly, some POMC neuronal progeni-
tors adopt a distinct fate, giving rise to antagonistic neu-
ronal populations expressing NPY [11]. Therefore, NPY
and POMC, which are expressed in mutually exclusive cell
populations in the adult hypothalamus, colocalize in a
subset of embryonic neuronal precursors [11].
Other hypothalamic cell populations are generated dur-
ing the embryonic period including ependymal cells, cuboid
ciliated cells that line the third ventricle (3V) wall of the
hypothalamus, formed at E16–E18 [14]. Tanycytes are spe-
cialized ependymal cells that are located in the floor of the
3V. In rodents, a subpopulation of radial glial cells (NPCs of
the embryonic brain) initiate their differentiation into tany-
cytes between E18 and the first postnatal days, and this
process is completed by the first month of life [14]. Tanycyte
Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2
functions are not clearly understood, but they seem to be
involved in feeding behavior as chemosensory cells and
adult NPCs that respond to diet alterations [14,15].
Impact of early nutritional and neurotrophic
environment
The nutritional and neurotrophic environment during the
embryonic period, when hypothalamic NPCs are develop-
ing, impacts upon the formation of an adequate NPC
population [16–18]. For example, offspring of dams with
higher body weight have a lower number of immature
neurons in the ARC [19]. Accordingly, proliferation of
hypothalamic NPCs in rodents during the perinatal period
is influenced by maternal diet manipulation and hormone
availability [16–18]. Specifically, offspring subjected to
nutritional restriction during the gestational period pres-
ent a reduced NPC population with decreased proliferative
capacity [16]; this results in body weight and feeding
deficits in newborns that persist after weaning [18,20].
By contrast, a maternal high-fat diet (HFD) regime pro-
motes the proliferation, differentiation, and migration of
orexigenic neuronal precursors in the hypothalamic PVN
of rats, increasing the density of orexigenic neurons in
newborns and leading to a higher risk of obesity [18].
A hypothesis has emerged from these findings that
hypothalamic neurogenesis during the neurodevelopment
period is crucial, and that conditions affecting neurogen-
esis during this period can modify the number of hypotha-
lamic NPCs and thus affect satiety pathways. As a
consequence, persistent changes on newborn homeostasis
and, possibly, reduced capacity to adapt to metabolic chal-
lenges during adulthood may be observed. In accordance,
this has been proposed as one possible mechanism respon-
sible for the high incidence of obesity in our society [21].
Transcriptional regulation of embryonic hypothalamic
neurogenesis
Several transcription factors have been identified as key
regulators of hypothalamic neurogenesis during the embry-
onic period [22–29]. For example, the proneural transcrip-
tion factor Mash1 (mammalian achaete-scute homolog 1) is
required for the generation of hypothalamic neurons, and
Mash1 null mice present severe hypoplasia of hypothalamic
nuclei including the ARC [26]. In addition, Mash1 and
neurogenin 3 (Ngn3) are involved in subtype specification
of neurons that are important for feeding regulation [26,27].
Mash1 is required for the differentiation of NPY-expressing
neurons and for the normal development of POMC neurons
[26]. By contrast, Ngn3 inhibits the expansion of the NPY
neuronal population and promotes the development of
POMC-expressing neurons [27].
The transcription factors single-minded homolog 1
(Sim1), aryl hydrocarbon receptor nuclear translocator 2
(ARNT2), and orthopedia (Otp) control the terminal differ-
entiation of neuroendocrine lineages within the PVN, in-
cluding the specification of corticotropin-releasing hormone
(CRH) and thyrotropin-releasing hormone (TRH) neurons
[22–25]. It has been reported that in mice null for either of
these genes, TRH and CRH neuroprecursors fail to differ-
entiate and produce hormones [22,24,25]. In addition, Sim1
heterozygous mice have a reduced total number of PVN
81
Review
neurons, including oxytocin neurons [30,31]. This develop-
mental defect impacts upon food intake regulation because
Sim1 heterozygous mice are hyperphagic and obese, a phe-
notype that can be reversed by oxytocin administration
[30,32].
Nescient helix-loop-helix (NHLH/NSCL) proteins 1 and 2
are neuronal transcription factors that control the develop-
ment of gonadotropin-releasing hormone (GnRH) neurons
in the hypothalamus [28,29]. NHLH2 and double NHLH1/2
knockout mice showed dramatic loss of GnRH neurons, most
likely due to deficient migration of neuroprogenitor cells to
the corresponding part of the hypothalamus [28,29].
Adult hypothalamic neurogenesis
Emerging evidence suggests that, in addition to the SVZ and
SGZ zones, active neurogenesis takes place in other regions
Box 1. Difficulties in the identification, localization, and determination of the proliferative capacity of hypothalamic NPCs
Endogenous and technical factors may contribute to conflicting data
on hypothalamic neurogenesis, and alternative approaches to over-
come these difficulties are needed.
Endogenous factors
Heterogeneous NPC population. Hypothalamic NPCs are a hetero-
geneous cellular population that includes a- and b-tanycytes [9,39,40],
subependymal astrocytes [42], and parenchymal progenitor cells [46];
these may represent subsets of NPCs in sequential differentiation states
[39,40]. The existence of NPC subsets within the hypothalamic
neurogenic niche may be a major internal factor underlying difficulties
in reaching a consensus about the origin and localization of these cells.
Genetic models allowing tracing of all neuroprogenitor cells (and not
only of specific cell types) may help to clarify this question.
Unknown NPC cell cycle. Putative hypothalamic NPC subsets may
have different cell cycle durations, as reported for other niches [67],
but this point needs investigation. Cell cycle length may determine
the number and subpopulation of cells labeled with BrdU. For
example, when BrdU is administered for only a brief period of time,
NPCs with a shorter cell cycle have a higher probability of
incorporating BrdU than other cells.
Technical factors
BrdU administration. Most proliferation studies evaluating hypotha-
lamic neurogenesis are based on the delivery of BrdU. However, BrdU
administration through specific routes (peripheral or intraventricular)
results in distinct labeling patterns, and these seem to reflect differing
BrdU availability to different types of cells [38]. Peripheral adminis-
tration of BrdU preferentially labels proliferative tanycytes in the
median eminence which are in close proximity to the peripheral blood
supply [9,39], whereas intracerebroventricular (i.c.v.) BrdU is prefer-
entially incorporated into proliferative cells in the 3V lateral wall and
hypothalamic parenchyma, possibly because these cells only have
access to BrdU in the CSF following i.c.v. administration [7,42].
Length and dosages of BrdU administration may interfere with
experimental observations [9,39]. For example, peripheral delivery
of BrdU for 15 days labels tanycytes of the median eminence and cells
in the hypothalamic parenchyma [39], whereas shorter periods of
administration failed to show parenchymal staining [9]. These
important factors vary considerably between studies and should be
considered when comparing experimental results.
BrdU labeling of non-proliferative cells. BrdU may be incorporated
in apoptotic or DNA-repairing cells [68–71], leading to possible
overestimation of proliferation rates in the hypothalamus (e.g.,
BrdU-positive neurons may be neurons undergoing apoptosis). This
is a crucial issue for models where hypothalamic neuronal degenera-
tion may be present, such as obesity [54,55]. To confirm that BrdU
incorporation is due to cell proliferation, double-labeling protocols
with BrdU and proliferation markers such as Ki-67 or PCNA can be
employed [33,71]. Another option is to confirm that cells marked with
82
Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2
of the adult rodent brain [33–36]. These regions include the
hypothalamus where a potential neurogenic niche has been
characterized [8,37–40]. Some reports suggest that the basal
(unstimulated) levels of neurogenesis in the hypothalamus
are low [37,38,40], and are probably less than those seen in
well-established neurogenic zones [35]. However, recent
papers have reported the contrary, and have shown robust
neurogenesis within the hypothalamus of mice under nor-
mal conditions [12,39]. These differences may be related to
the experimental approaches used to estimate the number
of new neurons in the hypothalamus and probably to the
identification of different NPC subsets by genetic and immu-
nolabeling techniques (Box 1). This is a crucial point, and
reconciling these differences will need further investigation.
Nevertheless, studies in support of the existence of basal
hypothalamic neurogenesis indicate that the adult rodent
BrdU are true newborn neurons by colabeling with doublecortin, a
transient marker of immature neurons that, in the SGZ cells,
disappears few weeks after birth [51].
Type of stimulus. Various stimuli have been used to induce
hypothalamic neurogenesis, including growth factors [7,37,40–42],
dietary manipulation [12,46], and injurious conditions [8,46]. It is
reasonable to assume that specific factors activate different NPC
subsets and, therefore, different cells types are eventually detected in
these studies.
Time-point of analysis. Analysis of neurogenesis using BrdU
incorporation or other methods is often performed at a single time-
point, which varies between studies. This is an important factor
because BrdU-labeled cells can be found in distinct hypothalamic
localizations depending on the length of time elapsed between BrdU
delivery and neurogenesis assessment [40,46]. In accordance, brain
examination immediately after BrdU infusion shows that most
positive cells are located in the ventricular wall [40], whereas long-
term analysis reveals an additional population of labeled cells in
subventricular layers [40] and an enriched number in the ARC [46].
Analyses of two time-points within each experiment can provide crucial
information about the localization of hypothalamic NPCs as well as the
neurogenesis process. For example, short-term BrdU analyses should
label immature precursor cells whereas later time-points may deter-
mine the localization of newly generated neurons [9,40,71].
Age of rodents. Postnatal neurogenesis studies have been
performed in rodents of different ages [8,9,37,40–42]. This is a crucial
aspect that may influence the data because the proliferative capacity
of hypothalamic NPCs decreases with age [12,39,53].
Technical artifacts. The experimental methods used to label NPCs
can introduce artifacts and make the interpretation of neurogenesis
studies difficult. For example, BrdU labeling is the most commonly
employed technique for assessing hypothalamic neurogenesis [7–
9,12,19,37–40,42,46], but the presence of incorporated BrdU mole-
cules within the cells may induce aberrant cellular proliferation,
migration, and differentiation [72,73]. In addition, genetic models
including viral vectors, Cre recombinase, and inducible Cre-recom-
binase systems have been used for long-term lineage tracing of
NPCs in the hypothalamus [9,19,39–41,46,50]. In general, genetic
technologies employ an endogenous promoter to drive the expres-
sion of a reporter gene, such as GFP or b-galactosidase, and mimic
the physiological expression patterns of a relevant gene. However,
discrepant expression patterns between reporter and endogenous
proteins [74,75] or incomplete labeling [19] have been described in
several models, raising the question on whether genetic models can
feasibly recapitulate endogenous neurogenesis processes. Never-
theless, genetic labeling of NPCs represents a valuable and useful
strategy, and the technical limitations can be minimized by careful
characterization of every model. For a detailed critical review about
the technical limitations of methods used to study neurogenesis see
[71].
 Review Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2

hypothalamus contains a resident population of NPCs
capable of generating new neurons [9,39–42]. In addition,
proliferative NPCs have also been observed in the adult
hypothalamus of other species including sheep [43], ham-
ster [44], and zebrafish [45].
Importantly, recent findings indicate that the adult
hypothalamic neurogenesis contributes to the regulation
of food intake [7–9]. For example, most of the newborn
hypothalamic progenitor cells follow a neuronal fate and
differentiate to phenotypes important for the regulation of
appetite, including NPY/AgRP- and POMC-expressing
neurons [7,8,19,37–39]. These new neurons are also re-
sponsive to fasting and leptin, characteristics of functional
hypothalamic neurons [7–9,19,39].
Cellular remodeling of feeding circuits, including re-
placement of mature POMC and NPY neurons, occurs
continuously during adulthood [12,46]. In young mice, half
of the NPY and POMC neurons are substituted by neurons
born postnatally within an 8 week period [12]. However,
neuronal turnover seems to slow down in adulthood
[12,46]. Noteworthy, this adult neurogenesis is important
because it is involved in the response of energy-balance
circuits to environmental and physiological challenges,
such as diet alterations, and possibly in replacing degen-
erative cells during adulthood [8,12,46].
The hypothalamic neurogenic niche
Two distinct ventricular proliferative zones in the hypo-
thalamus have been described (Figure 1) – the medial part
of the 3V wall, with proliferative tanycytes and prolifer-
ative subependymal astrocytes [40,42], and the ventral
part of the 3V wall (median eminence), which includes
proliferative tanycytes [9,39]. Moreover, evidence sug-
gests that newborn neurons originating from the ventric-
ular proliferative cells migrate to the hypothalamic
parenchyma where they are incorporated into the appetite
circuits [19,39,41] (Figure 1).
Tanycytes are considered to be adult hypothalamic
NPCs in view of their proliferative capacity both in basal
and stimulated conditions [9,39,40]. They express the neu-
roprogenitor markers vimentin and nestin, and are classi-
fied in two major subpopulations: a-tanycytes (in the
lateral 3V wall) and b-tanycytes (in the median eminence)
[14,40]. Astrocytes in the subependymal layers are also
regarded as possible adult hypothalamic NPCs because
they share common features with neural stem cells from
the SVZ [47], including subependymal localization, stain-
ing for glia-specific markers, and increased proliferation
upon growth factor stimulation [42].
The shape and location of proliferative hypothalamic
NPCs (tanycytes and subependymal astrocytes) places
them in a strategic position to sense and integrate periph-
eral metabolic alterations (Figure 1). For example, tany-
cytes lying on the median eminence have privileged access,
via fenestrated capillaries, to nutritional signals carried by
the bloodstream such as glucose and hormones [14]. More-
over, tanycyte cell bodies that line the lateral wall of the 3V
and subependymal astrocytes, via a cellular process that
protrude the ependymal cell layer, are in contact with the
cerebrospinal fluid (CSF) and molecules present in this
fluid [14,42]. In addition, tanycytes have a long basal
process that penetrates into the hypothalamic parenchyma
and allows close proximity to energy-sensing neurons [14].
The proximity of hypothalamic NPCs to nutritional cues
is an important factor supporting the putative role of neu-
rogenesis in feeding regulation because NPC proliferation
and differentiation to neuronal phenotypes could then be
controlled by cues that signal the metabolic needs of the
organism. Indeed, several lines of evidence indicate that
hypothalamic NPCs can sense and respond to peripheral

Key:
Tanycyte
3V wall PVN
Dorsal CRH LH Proliferave tanycyte
TRH
ORX
Ependymal cell
(C)
? MCH
(A) Proliferave subependymal astrocyte
Medial
Subependymal cell

POMC Proliferave cell in the hypothalamic

3V
(B) Ventral NPY/AGRP parenchyma
ARC
Hypothalamic neuron
Median eminence
Migraon Integraon

TRENDS in Endocrinology & Metabolism

Figure 1. Schematic representation of the hypothalamic neurogenic niche in the adult rodent brain. The third ventricle (3V) wall is constituted by ependymal cells (light
grey), tanycytes (blue), and subependymal cells (dark brown). There are different proliferative zones on the 3V wall: (A) the medial part, containing proliferative tanycytes
and proliferative subependymal astrocytes (light and dark green, respectively); and (B) the ventral part (median eminence), containing proliferative tanycytes (light green)
[9,42]. The ventricular neuroprogenitor cells migrate to the hypothalamic parenchyma (green arrow) and are incorporated in the appetite circuits (red arrows) [41]. (C)
Proliferative cells are also present in the hypothalamic parenchyma (green) [46]; these cells may represent a cellular subtype generated from ventricular progenitor cells
[50]. Hypothalamic neurons (red) express different neuropeptides important for the regulation of feeding and are located in hypothalamic nuclei (grey). Cellular processes
are not represented. Abbreviations: AgRP, agouti-related protein; ARC, arcuate nucleus; CRH, corticotropin-releasing hormone; LH, lateral hypothalamus; MCH, melanin
concentrating hormone; NPY, neuropeptide Y; ORX, orexin; POMC, proopiomelanocortin; PVN, paraventricular nucleus; TRH, thyrotropin-releasing hormone; 3V, third
ventricle.

83
Review
nutritional signals [9,12,46,48,49]. For example, tanycytes
have chemosensory properties for glucose, hormones, and
neurotrophic factors that activate intracellular pathways
[48,49]. In addition, energy-balance alterations, such as
HFD regime and caloric restriction, can modify the prolifer-
ation rates and differentiation of hypothalamic NPCs
[9,12,46]. However, the cellular mechanisms that can stim-
ulate or inhibit the division and differentiation of hypotha-
lamic NPCs are unknown; this hypothesis is therefore not
fully validated but represents an emerging area of investi-
gation.
There is no consensus about the identity of adult
hypothalamic NPCs. For example, a recent report iden-
tifies the ventral b-tanycytes as hypothalamic NPCs be-
cause they proliferate in basal conditions and their
neuronal descendants populate the hypothalamus of
young adult mice [9,39]. However, another study showed
that lateral a-tanycytes are the key components of this
neurogenic niche [40]. Moreover, each of these two reports
excluded the other tanycyte subtype as potential hypo-
thalamic NPCs [39,40]. Interestingly, although both stud-
ies are based on mouse models with tanycyte-specific Cre
recombinase expression, the different promoters driving
Cre expression were specific for different tanycyte sub-
populations, and this may account for the conflicting
results [39,40]. Another possibility is that a- and b-tany-
cytes represent functionally distinct NPC subsets, or
possibly NPCs in sequential differentiation states, be-
cause a-tanycytes can give rise to more ventrally located
b-tanycytes [40].
The hypothalamic parenchyma may also harbor divid-
ing NPCs because proliferating cell ‘pairs’ were observed
interiorly to the ventricular zones [8,37–39] (Figure 1).
Furthermore, studies based on the stem cell marker SOX2
revealed a significant number of NPCs within the mouse
hypothalamic parenchyma under normal conditions
[39,46]. Parenchymal proliferative cells may arise from
the cellular division of ventricular progenitors that mi-
grate inwardly during the differentiation process [50]
(Figure 1). In agreement, descendents of ventricular b-
tanycytes can remain undifferentiated and continue to
divide within the hypothalamic parenchyma [39]. Howev-
er, because the cellular origin of most parenchymal prolif-
erative cells is still unknown this hypothesis requires
further investigation. In addition, BrdU (bromodeoxyur-
idine, a thymidine analog that is selectively incorporated
by dividing cells) injected into the 3 V labels a greater
number of cells in the hypothalamic parenchyma than in
the ventricular zone [7,37,39,46], suggesting that paren-
chymal dividing cells may not originate from the prolifer-
ation of ventricular NPCs. Collectively, these data suggest
that hypothalamic parenchymal NPCs have a shorter cell
cycle and incorporate BrdU faster than ventricular cells.
This raises the hypothesis that parenchymal NPCs con-
stitute a specific cell subset (which may or may not be
derived from the ventricular zone) which, because of their
location, can respond more rapidly to metabolic signals by
proliferating and differentiating to new neurons within
the hypothalamus.
In summary, although several studies have reported
on the identity, location, and proliferative capacity of
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Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2
hypothalamic NPCs [9,38–40,42,46], the often conflicting
findings warrant further investigation.
Adult hypothalamic neurogenesis and the role of neural
growth factors
In rodents, neurogenesis in the adult hypothalamus is
enhanced by intraventricular administration of neural
growth factors (Table 1); these factors drive a higher
percentage of cells towards the neuronal phenotype com-
pared to endogenous neurogenesis [7,37,42]. Moreover, the
identity of proliferative hypothalamic cells as newborn
neurons was confirmed by colabeling with BrdU and dou-
blecortin (transient marker of immature neurons [51]) [7].
More importantly, ciliary neurotrophic factor (CNTF)
promotes reductions in food intake and weight gain in diet-
induced obese mice that persist after treatment withdraw-
al and are reversed upon inhibition of cell proliferation [7],
suggesting that a mechanism by which CNTF promotes
long-term weight loss is by enhancing hypothalamic neu-
rogenesis [7]. Inhibition of cell proliferation in the ventral
regions of the hypothalamus (ARC and median eminence)
also results in weight loss and food intake deficits in mice
[8,9]. These data suggest that neurogenesis is part of the
hypothalamic mechanisms that regulate energy-balance.
Endogenous growth factors may also be important med-
iators of hypothalamic neurogenesis [52]. For example,
intraventricular infusion of brain-derived neurotrophic
factor (BDNF) or insulin-like growth factor 1 (IGF-1)
(growth factors that are also expressed endogenously in
the hypothalamus, as well as their receptors), activates
the production of new neurons in this region [7,37,42].
Moreover, GnRH, which is expressed by hypothalamic
neurons, can promote the proliferation and survival of
NPCs in the hypothalamus of aged mice [53]. Thus, neu-
rogenesis activation by endogenous molecules may consti-
tute a physiological mechanism to respond to metabolic
challenges, helping to modulate feeding circuits appropri-
ately throughout adult life. However, it remains unclear
if metabolic cues, such as moderate disturbances in
energy-balance, can trigger a compensatory upregulation
of neurotrophic factors (or other molecules) in the
hypothalamus.
Interestingly, growth factors induce different levels of
neurogenesis in different hypothalamic nuclei [8,37,42].
For example, IGF-1 administration induces neurogenesis
in the medial periventricular and parenchymal zones [42]
and BDNF infusion leads to high density of new cells in the
PVN [37]. Finally, degeneration of AgRP neurons increases
cell proliferation exclusively in the ARC [8]. Collectively,
these observations highlight a pattern of region-specific
activation of hypothalamic neurogenesis which might be
influenced by the energy status of the organism.
Impact of energy-balance disorders on adult
hypothalamic neurogenesis
Neurogenesis in the adult hypothalamus is modulated by
cellular dysfunction such as neuronal cell loss, obesity-
induced inflammation, and neurodegeneration [6,8,12,46].
Obesity and HFD induce hypothalamic injuries in rodents
and humans, including activation of inflammatory and
endoplasmic reticulum stress pathways, microglia and
Review Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2

Table 1. Activation of adult hypothalamic neurogenesis by growth factors and correlation with receptors in rodentsa
Stimulus Administration Hypothalamic neurogenesis Localization of prolifer- Correlation with receptors Refs
ative cells
BDNF I.c.v. infusion Increases cell proliferation (BrdU+ cells) Diffusely in the Newborn cells do not [37]
for 12 days hypothalamus express BDNF receptor
A significant percentage of new cells are parenchyma
neurons Localization of newborn
High density in the PVN cells and BDNF receptors
More new neurons in the PVN than in the correlate strongly
SVZ
CNTF I.c.v. infusion Increases cell proliferation (BrdU+ cells) Diffusely in the Some newborn cells [7]
for 7 days hypothalamus express CNTF receptor
A significant percentage of new cells are parenchyma
neurons (including NPY and POMC Localization of newborn
neurons) High density in the ARC cells and CNTF receptors
and median eminence correlate strongly
Some new cells are oligodendrocytes
IGF-1 I.c.v. infusion Increases cell proliferation (BrdU+ cells) High density in the Some newborn cells [42]
for 7 days hypothalamus express IGF-1 receptor in
A significant percentage of new cells are parenchyma and in the the periventricular zone
neurons caudal periventricular
zone Localization of newborn
cells and IGF-1 receptors
correlate strongly
FGF, EGF, and Single injection Increases cell proliferation (BrdU+ and 3V wall (2–3 cell layers in FGF receptors are [41]
FGF+EGF directly into nestin+ cells) the ependymal layer) expressed in the cells of
the 3V the 3V wall
FGF is more potent in inducing
hypothalamic neurogenesis

Newborn cells are astrocytes and neurons

(including orexin-A neurons)
EGF+FGF Subcutaneous Increases cell proliferation (BrdU+ cells) ARC parenchyma N/A [60]
injection for
10 days Promotes hypothalamic neuronal
repopulation upon acute toxic effect of
glutamate
FGF I.c.v. infusion Increases cell proliferation (BrdU+ cells) In the medial part of the 3V FGF-10 and FGF-18 are [40]
for 7 days wall expressed within tanycyte-
Newborn cells are vimentin+ tanycytes (in containing regions
the 3V wall) Sub/periventricular zone
a
Abbreviations: ARC, arcuate nucleus; BDNF, brain-derived neurotrophic factor; BrdU, bromodeoxyuridine; CNTF, ciliary neurotrophic factor; EGF, epidermal growth factor;
FGF, fibroblast growth factor; I.c.v., intracerebroventricular; IGF-1, insulin-like growth factor 1; N/A, not studied; PVN, paraventricular nucleus; 3V, third ventricle.

astrocyte activation, and neuronal cell death [54–56]. It
was recently shown that obesity also inhibits adult hypo-
thalamic neurogenesis (Figure 2), resulting in reduced
generation of new neurons, including NPY and POMC
neurons, in addition to decreased proliferative capacity
of hypothalamic NPCs [12,46]. Further, a HFD regime
in mice restrains the constitutive self-renewal capacity
of NPY and POMC neurons by promoting the retention
of old neurons and the apoptosis of newborn neurons [12].
Conversely caloric restriction has the opposite effect and is
able to reverse the reduction in hypothalamic neurogenesis
in obese mice [12].

(A) Acvaon Inhibion (B)

Physiological Pathology
response Endogenous hypothalamic neurogenesis

Energy balance

Homeostasis Defecve

Smulus: • Mild neuronal loss • Severe neuronal loss

• Growth factors • Obesity-induced inflammaon

TRENDS in Endocrinology & Metabolism

Figure 2. Endogenous hypothalamic neurogenesis contributes to the regulation of energy-balance. (A) Hypothalamic neurogenesis is stimulated by growth factors or mild
neuronal loss to re-establish homeostasis as a physiological response [7,8]. (B) Hypothalamic neurogenesis is inhibited by severe neuronal loss or obesity-induced
inflammation, contributing to a defective energy-balance in pathological conditions [12,46].

85
Review
In addition to hypothalamic neuronal cell loss [54,55],
obesity may further exacerbate this damage by promoting
a reduction in the levels of neuron replacement. Indeed,
adult hypothalamic NPCs are vulnerable to HFD-induced
inflammation, including IKKB/NF-kB upregulation [46].
These inflammatory mediators are responsible for inhibit-
ing the survival and proliferation of adult hypothalamic
NPCs and inducing neuronal differentiation deficits in
these cells [46]. It should be noted that selective over-
expression of IKKB in hypothalamic NPCs is sufficient
to impair neurogenesis and induce obesity in adult mice on
normal chow diet [46].
Genetic obesity is also associated with defective remo-
deling of feeding circuits, and obese leptin-deficient (ob/ob)
mice reveal decreased hypothalamic neurogenesis [12].
However, it is possible that ob/ob mice exhibit fewer NPCs
as a result of the absence of leptin, which is known to
stimulate the proliferation of hypothalamic NPCs both in
vivo and in vitro [12,16].
It was recently reported that hypothalamic neurogen-
esis is reduced in aged mice [53], which is of interest
because aging is associated with increased risk of obesity
and neuroinflammation [57,58]. This putative link be-
tween obesity, aging, and hypothalamic neurogenesis war-
rants further investigation.
The effects of obesity on hypothalamic neurogenesis
may be more complex because a recent investigation shows
that HFD consumption increases the neurogenic rates in
the hypothalamus of adult mice, whereas selective loss of
the median eminence neurogenic niche protects from ex-
cessive weight-gain upon HFD feeding [9]. In particular,
hypothalamic neurogenesis was increased in mice under a
shorter HFD period (1 month) [9]. Therefore, a possible
explanation for these contradictory findings is that altera-
tions in neurogenesis follow an activation–inhibition pat-
tern, because this is known to take place for other
hypothalamic mechanisms following HFD consumption
[54] (Figure 2). Thus, this latter study may be reporting
an early compensatory activation of hypothalamic neuro-
genesis promoted by mild neuronal loss – which is known
to occur upon HFD consumption [55]. This event can
stimulate neurogenesis in the hypothalamus, as reported
in mouse models of neurodegeneration [8].
Accordingly, HFD has a transient effect in hypothalamic
cell renewal, with a proliferation peak occurring 3 days
after the introduction of HFD, followed by a gradual re-
duction over time [6]. A possible reason for this rapid effect
includes direct activation of NPC division by nutritional
cues or inflammatory mediators, which are elevated within
1–3 days of HFD onset [54].
Several lines of evidence suggest that adult hypotha-
lamic neurogenesis can constitute an early protective
mechanism to preserve homeostasis under detrimental
nutritional conditions (Figure 2) [6,8]. For example, block-
ing cerebral cell proliferation during the initial period of
HFD-stimulated neurogenesis accelerates weight gain and
obesity onset in mice [6]. Moreover, HFD regime increases
the percentage of neurons adopting the anorexigenic
POMC phenotype, suggesting that the maturation of neu-
rons in feeding circuits is nutritionally regulated to pre-
vent further weight gain [6]. Finally, another study showed
86
Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2
that progressive neurodegeneration of NPY/AgRP neurons
in mutant mice leads to increased hypothalamic cell pro-
liferation [8] in an effort to maintain energy-balance. If
hypothalamic cell proliferation is blocked, the decrease in
food intake and body adiposity in these mice can be detri-
mental [8].
In summary, several stimuli promoting hypothalamic
cell proliferation scenarios have been identified, and in-
clude mild neuronal cell loss and upregulation of neuro-
trophic factors [7,8] (Figure 2). Notably, energy-balance
can be re-established upon activation of hypothalamic
neurogenesis by these stimuli [7,8]. Therefore, we suggest
that modulation of hypothalamic neurogenesis, and stim-
ulation of a self-repair system driven by resident NPCs,
may provide potential therapies for disorders affecting the
hypothalamus. This strategy is already being investigated
for other neurogenic regions [59]. Endogenous molecules
that can activate the hypothalamic neurogenic niche are
evident candidates for therapeutic objectives. This seems
to be a promising strategy because peripheral administra-
tion of growth factor has been shown to repopulate the
hypothalamic ARC upon acute loss of hypothalamic neu-
rons induced by glutamate insult [60]. Nevertheless, more
research is needed to fine-tune the induction of cell prolif-
eration (and subsequent cell differentiation) and selective
modulation of food intake and body weight.
Concluding remarks
The concept of adult hypothalamic neurogenesis has chan-
ged the paradigm of how we understand energy-balance
regulation. It is now widely accepted that neurogenic
processes occurring in the adult rodent hypothalamus
contribute to the physiological regulation of food intake
and body weight. Mechanistically, this neuronal plasticity
offers the organism flexibility to respond/adapt to daily
metabolic challenges. However, the exact role of adult
hypothalamic neurogenesis in feeding regulation can only
be clearly demonstrated after specific ablation of newly
formed neurons in this region. This may be possible by
using genetic strategies similar to those that revealed the
functional/structural importance of hippocampal neuro-
genesis [61,62].
There are other relevant topics that need further inves-
tigation before the basis of hypothalamic neurogenesis can
be unraveled. These include the need to clarify the origin of
putative NPC subsets, to identify the endogenous factors
that promote NPC proliferation/differentiation, and to
determine the basal rates of neurogenesis in the hypothal-
amus.
Drawing from previous work on the SVZ and SGZ
[61,63], another key experiment would be to follow geneti-
cally labeled hypothalamic NPCs from early postnatal
days until adulthood, and to elucidate the proliferation,
migration, and differentiation processes of these cells.
However, the challenge is to find a promoter to drive
transgene expression that is widely and actively expressed
in hypothalamic NPCs and that can be used as a marker in
genetic strategies. One candidate for such a marker is
nestin, an intermediate filament protein often used to label
neural stem cells [64]; apparently, nestin is expressed in
hypothalamic NPCs including tanycytes (a and b) and
Review
Box 2. Outstanding questions
 Does the human adult hypothalamus contain NPCs? Is hypotha-
lamic neurogenesis an endogenous mechanism contributing to
energy-balance in humans? Does obesity cause defects in
hypothalamic neurogenesis in humans?
 What mechanisms are associated with the activation of endogen-
ous hypothalamic neurogenesis in response to homeostatic
challenges? Is there an upregulation of neurotrophic factors
mediating this effect?
 Can energy-balance be re-established upon therapeutic activation
of hypothalamic neurogenesis? Will it be possible to obtain a
predicable effect on food intake and body weight? Can neuro-
trophic factors be used for stimulation of endogenous hypotha-
lamic NPCs?
 What conditions/molecules affect hypothalamic neurogenesis
during the perinatal period? How do these conditions/molecules
modify the programming of hypothalamic satiety pathways? Will
this lead to changes in homeostasis that persistent in adulthood?
Are these changes responsible for the high incidence of obesity in
our society?
 Can embryonic hypothalamic neurogenesis be modulated for
postnatal therapeutic objectives? Would it be possible to program
the hypothalamus during the perinatal period in an effort to make
individuals less prone or resistant to obesity? Will it be possible to
reprogram the adult hypothalamus to reduce or prevent obesity?
SOX2-positive parenchymal cells [39,40,46,65]. Unfortu-
nately, the existing transgenic mouse models revealed a
discordant pattern of nestin expression and variable num-
bers of nestin-positive cells within the hypothalamus
[9,46]. It is crucial to recognize that NPCs are a heteroge-
neous cell population and that different proliferative zones
may exist within the hypothalamus; careful design of
future studies will be necessary to obtain new reliable
information about the hypothalamic neurogenic niche
and to reconcile existing contradictory findings.
Another important consideration is that the current
studies were based solely on rodent models, and the rele-
vance of key observations for human physiology needs to be
established. Although many crucial questions remain un-
answered (Box 2), the idea of exploiting hypothalamic
neurogenesis therapeutically for diseases such as obesity
is innovative and exciting.
Acknowledgments
We thank the FCT (Portuguese Foundation for Science and Technology),
FEDER (Fundo Europeu de Desenvolvimento Regional), and COMPETE
(Programa Operacional Factores de Competitividade) for financial
support (SFRH/BPD/4/2011; PEst-C/SAU/LA0001/2013-2014; PTDC/
SAU-FCF/099082/2008).
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