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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 A new neural stem/progenitor cell niche has recently
adult hypothalamus, the center for energy regulation, been described to reside in the adult hypothalamus, a
suggests that hypothalamic neurogenesis is a crucial part brain region that functions as the central regulator of
of the mechanisms that regulate food intake. Accordingly, homeostasis by controlling food intake, metabolism, and
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 Glossary
energy-balance. This review critically discusses recent Arcuate nucleus (ARC): a region of the hypothalamus where the nutrient-
findings on the contribution of adult hypothalamic neu- sensing neurons are located.
Ependymal cells: cubic ciliated cells that line the ventricles (cavities) of the brain.
rogenesis to feeding regulation, the impact of energy- In addition to barrier functions, ependymal cells are involved in the production
balance disorders on adult hypothalamic neurogenesis, and circulation of the CSF. In the hypothalamus, ependymal cells are the interface
and the influence of embryonic hypothalamic neurogen- between the third ventricle (3V) and hypothalamus parenchyma.
Feeding regulation: a complex mechanism that includes central processes that
esis upon feeding regulation in the adult. Understanding take place in the hypothalamus. In brief, ARC neurons receive peripheral signals
how hypothalamic neurogenesis contributes to food regarding the energy status of the organism and synthesize neuropeptides in
response to those signals. The neuropeptides help in integrating and translating
intake control will change the paradigm on how we
those signals into motivated behavior. Usually, hypothalamic responses
perceive energy-balance regulation. counteract the nutritional signals to re-establish energy homeostasis.
Growth factors: molecules that increase the generation and/or survival of
Neurogenesis in the adult brain progenitor neuronal cells in neurogenic areas of the adult brain.
Hypothalamus: a brain area responsible for feeding regulation and
Neurogenesis is a complex and highly regulated process metabolism. It consists of several regions (nuclei) with different neuronal
that results in the production of new neurons (see populations that express specific neuropeptides. The hypothalamus is located
Glossary). Neurogenesis occurs at high rates during the in close proximity to the 3V.
Hypothalamic neurogenesis: the generation of new neurons in the adult or
embryonic period when substantial quantities of new cells embryonic hypothalamus that arise from the proliferation and differentiation of
are generated by the proliferation of neuroprogenitor cells hypothalamic NPCs.
Leptin: an anorexigenic hormone released from adipocytes into the circulation
(NPCs), and subsequently migrate to the developing tis-
as a function of body fat content. High levels of fat storage raise the
sue [1]. In the adult, neurogenesis occurs at low rates in concentrations of leptin, and leptin suppresses food intake by inhibiting
discrete regions of the brain such as the subventricular NPY/AgRP neurons and activating POMC neurons.
Neurogenesis: the set of events leading to the production of new neurons from
zone (SVZ) of the lateral ventricles and the subgranular NPCs. This process includes division (proliferation) of NPCs, migration,
zone (SGZ) of the hippocampus [2]. NPCs from these maturation (differentiation to a specific neuronal type), and functional
regions proliferate and migrate to their final destination, integration of the new neurons into existing neuronal circuits.
Neurogenic niche: the zone(s) in the adult brain where NPCs are retained after
the olfactory bulb and the granule cell layer of the dentate embryonic development. The microenvironment in the neurogenic niche,
gyrus, respectively, where they differentiate to form new including cell–cell interactions, can retain the NPCs in the undifferentiated state
neurons and integrate into pre-existing circuits [3]. Im- and regulate the proliferation and differentiation of NPCs [66].
Neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons: a group of
portantly, neurogenesis is not simply a restorative mech- neurons located in the ARC that express NPY and AgRP; these neuropeptides
anism; it represents a functional response of the organism have orexigenic actions (increase food intake) and are activated during energy
to daily challenges imposed by environmental and inter- deficiency.
Neuroprogenitor cells (NPC): the population of cells with proliferative and self-
nal states [2]. Moreover, the new neurons produced renewal capacity that can differentiate to different neural phenotypes.
through the adult life seem to contribute to behavioral Paraventricular nucleus (PVN): region of the hypothalamus that receives most
functions such as learning, memory consolidation, and of the neuronal projections from the ARC neurons.
Proopiomelanocortin (POMC) neurons: a group of neurons located in the ARC
mood regulation [3]. 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.
Corresponding author: Cavadas, C. (ccavadas@uc.pt).
Subependymal astrocytes: glial cells located beneath the ependymal layer of
Keywords: hypothalamus; neurogenesis; neural stem cells; food intake; obesity;
the 3V wall that present features of neural stem cells, including expression of glial
neuropeptide Y; proopiomelanocortin.
fibrillary acidic protein (GFAP) and proliferation upon growth factor stimulation.
1043-2760/$ – see front matter Therefore, subependymal astrocytes are identified as adult hypothalamic NPCs.
ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2013.10.005 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.

80 Trends in Endocrinology and Metabolism, February 2014, Vol. 25, No. 2


Review Trends in Endocrinology and Metabolism February 2014, Vol. 25, No. 2

body temperature, among other functions. Emerging evi- functions are not clearly understood, but they seem to be
dence discussed in detail below suggests that these adult- involved in feeding behavior as chemosensory cells and
born hypothalamic neurons play a crucial role in feeding adult NPCs that respond to diet alterations [14,15].
regulation, underscoring their significance in the central
control of energy-balance. Impact of early nutritional and neurotrophic
environment
Hypothalamus and feeding regulation The nutritional and neurotrophic environment during the
Feeding behavior and energy-balance are regulated cen- embryonic period, when hypothalamic NPCs are develop-
trally by the hypothalamus. Distinct nuclei within the ing, impacts upon the formation of an adequate NPC
hypothalamus, including the arcuate nucleus (ARC), the population [16–18]. For example, offspring of dams with
paraventricular nucleus (PVN), the ventromedial (VMH) higher body weight have a lower number of immature
and dorsomedial (DMH) hypothalamus, and the lateral neurons in the ARC [19]. Accordingly, proliferation of
hypothalamic area, share neuronal interconnections hypothalamic NPCs in rodents during the perinatal period
and together they maintain body homeostasis [4]. ARC is influenced by maternal diet manipulation and hormone
neurons produce the orexigenic neuropeptides neuropep- availability [16–18]. Specifically, offspring subjected to
tide Y (NPY) and agouti-related protein (AgRP) that act to nutritional restriction during the gestational period pres-
increase food intake, and the anorexigenic neuropeptide ent a reduced NPC population with decreased proliferative
proopiomelanocortin (POMC), the product of which (a- capacity [16]; this results in body weight and feeding
MSH) acts to decrease food intake [5]. The activity of deficits in newborns that persist after weaning [18,20].
ARC neurons is regulated by metabolic peripheral signals By contrast, a maternal high-fat diet (HFD) regime pro-
including hormones and gastrointestinal peptides [4]. For motes the proliferation, differentiation, and migration of
example, the adipose-derived hormone leptin, which is orexigenic neuronal precursors in the hypothalamic PVN
produced in proportion to body fat content, can activate of rats, increasing the density of orexigenic neurons in
the leptin receptors present in ARC neurons [4] to increase newborns and leading to a higher risk of obesity [18].
the expression and release of POMC and reduce the ex- A hypothesis has emerged from these findings that
pression and release of NPY, resulting in a decrease in food hypothalamic neurogenesis during the neurodevelopment
intake [5]. More recently, neurogenesis has been described period is crucial, and that conditions affecting neurogen-
in the hypothalamus and has been shown to participate in esis during this period can modify the number of hypotha-
the response of hypothalamic neuronal circuits to meta- lamic NPCs and thus affect satiety pathways. As a
bolic signals [6–9]. consequence, persistent changes on newborn homeostasis
and, possibly, reduced capacity to adapt to metabolic chal-
Embryonic hypothalamic neurogenesis influences adult lenges during adulthood may be observed. In accordance,
feeding regulation this has been proposed as one possible mechanism respon-
Cell populations during embryonic hypothalamic sible for the high incidence of obesity in our society [21].
neurogenesis
The development of hypothalamic feeding circuits starts Transcriptional regulation of embryonic hypothalamic
during the embryonic period and, in rodents, continues neurogenesis
through the first 2 weeks of postnatal life [10]. Recent Several transcription factors have been identified as key
studies show that hypothalamic NPCs are present in the regulators of hypothalamic neurogenesis during the embry-
embryonic hypothalamus; for example, in rodents, POMC onic period [22–29]. For example, the proneural transcrip-
and NPY neuroprecursors are identified as early as em- tion factor Mash1 (mammalian achaete-scute homolog 1) is
bryonic (E) days E10.5 and E14.5, respectively [11,12]. In required for the generation of hypothalamic neurons, and
agreement, NPCs isolated from fetal rat hypothalamus Mash1 null mice present severe hypoplasia of hypothalamic
express neuropeptides NPY, AgRP, and POMC [13]. Im- nuclei including the ARC [26]. In addition, Mash1 and
portantly, the number of immature POMC neurons in the neurogenin 3 (Ngn3) are involved in subtype specification
ARC triples and reaches its adult number during the fetal of neurons that are important for feeding regulation [26,27].
period [11]. Surprisingly, some POMC neuronal progeni- Mash1 is required for the differentiation of NPY-expressing
tors adopt a distinct fate, giving rise to antagonistic neu- neurons and for the normal development of POMC neurons
ronal populations expressing NPY [11]. Therefore, NPY [26]. By contrast, Ngn3 inhibits the expansion of the NPY
and POMC, which are expressed in mutually exclusive cell neuronal population and promotes the development of
populations in the adult hypothalamus, colocalize in a POMC-expressing neurons [27].
subset of embryonic neuronal precursors [11]. The transcription factors single-minded homolog 1
Other hypothalamic cell populations are generated dur- (Sim1), aryl hydrocarbon receptor nuclear translocator 2
ing the embryonic period including ependymal cells, cuboid (ARNT2), and orthopedia (Otp) control the terminal differ-
ciliated cells that line the third ventricle (3V) wall of the entiation of neuroendocrine lineages within the PVN, in-
hypothalamus, formed at E16–E18 [14]. Tanycytes are spe- cluding the specification of corticotropin-releasing hormone
cialized ependymal cells that are located in the floor of the (CRH) and thyrotropin-releasing hormone (TRH) neurons
3V. In rodents, a subpopulation of radial glial cells (NPCs of [22–25]. It has been reported that in mice null for either of
the embryonic brain) initiate their differentiation into tany- these genes, TRH and CRH neuroprecursors fail to differ-
cytes between E18 and the first postnatal days, and this entiate and produce hormones [22,24,25]. In addition, Sim1
process is completed by the first month of life [14]. Tanycyte heterozygous mice have a reduced total number of PVN
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neurons, including oxytocin neurons [30,31]. This develop- of the adult rodent brain [33–36]. These regions include the
mental defect impacts upon food intake regulation because hypothalamus where a potential neurogenic niche has been
Sim1 heterozygous mice are hyperphagic and obese, a phe- characterized [8,37–40]. Some reports suggest that the basal
notype that can be reversed by oxytocin administration (unstimulated) levels of neurogenesis in the hypothalamus
[30,32]. are low [37,38,40], and are probably less than those seen in
Nescient helix-loop-helix (NHLH/NSCL) proteins 1 and 2 well-established neurogenic zones [35]. However, recent
are neuronal transcription factors that control the develop- papers have reported the contrary, and have shown robust
ment of gonadotropin-releasing hormone (GnRH) neurons neurogenesis within the hypothalamus of mice under nor-
in the hypothalamus [28,29]. NHLH2 and double NHLH1/2 mal conditions [12,39]. These differences may be related to
knockout mice showed dramatic loss of GnRH neurons, most the experimental approaches used to estimate the number
likely due to deficient migration of neuroprogenitor cells to of new neurons in the hypothalamus and probably to the
the corresponding part of the hypothalamus [28,29]. identification of different NPC subsets by genetic and immu-
nolabeling techniques (Box 1). This is a crucial point, and
Adult hypothalamic neurogenesis reconciling these differences will need further investigation.
Emerging evidence suggests that, in addition to the SVZ and Nevertheless, studies in support of the existence of basal
SGZ zones, active neurogenesis takes place in other regions hypothalamic neurogenesis indicate that the adult rodent

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 BrdU are true newborn neurons by colabeling with doublecortin, a
on hypothalamic neurogenesis, and alternative approaches to over- transient marker of immature neurons that, in the SGZ cells,
come these difficulties are needed. disappears few weeks after birth [51].
Type of stimulus. Various stimuli have been used to induce
Endogenous factors hypothalamic neurogenesis, including growth factors [7,37,40–42],
Heterogeneous NPC population. Hypothalamic NPCs are a hetero- dietary manipulation [12,46], and injurious conditions [8,46]. It is
geneous cellular population that includes a- and b-tanycytes [9,39,40], reasonable to assume that specific factors activate different NPC
subependymal astrocytes [42], and parenchymal progenitor cells [46]; subsets and, therefore, different cells types are eventually detected in
these may represent subsets of NPCs in sequential differentiation states these studies.
[39,40]. The existence of NPC subsets within the hypothalamic Time-point of analysis. Analysis of neurogenesis using BrdU
neurogenic niche may be a major internal factor underlying difficulties incorporation or other methods is often performed at a single time-
in reaching a consensus about the origin and localization of these cells. point, which varies between studies. This is an important factor
Genetic models allowing tracing of all neuroprogenitor cells (and not because BrdU-labeled cells can be found in distinct hypothalamic
only of specific cell types) may help to clarify this question. localizations depending on the length of time elapsed between BrdU
Unknown NPC cell cycle. Putative hypothalamic NPC subsets may delivery and neurogenesis assessment [40,46]. In accordance, brain
have different cell cycle durations, as reported for other niches [67], examination immediately after BrdU infusion shows that most
but this point needs investigation. Cell cycle length may determine positive cells are located in the ventricular wall [40], whereas long-
the number and subpopulation of cells labeled with BrdU. For term analysis reveals an additional population of labeled cells in
example, when BrdU is administered for only a brief period of time, subventricular layers [40] and an enriched number in the ARC [46].
NPCs with a shorter cell cycle have a higher probability of Analyses of two time-points within each experiment can provide crucial
incorporating BrdU than other cells. information about the localization of hypothalamic NPCs as well as the
neurogenesis process. For example, short-term BrdU analyses should
Technical factors label immature precursor cells whereas later time-points may deter-
BrdU administration. Most proliferation studies evaluating hypotha- mine the localization of newly generated neurons [9,40,71].
lamic neurogenesis are based on the delivery of BrdU. However, BrdU Age of rodents. Postnatal neurogenesis studies have been
administration through specific routes (peripheral or intraventricular) performed in rodents of different ages [8,9,37,40–42]. This is a crucial
results in distinct labeling patterns, and these seem to reflect differing aspect that may influence the data because the proliferative capacity
BrdU availability to different types of cells [38]. Peripheral adminis- of hypothalamic NPCs decreases with age [12,39,53].
tration of BrdU preferentially labels proliferative tanycytes in the Technical artifacts. The experimental methods used to label NPCs
median eminence which are in close proximity to the peripheral blood can introduce artifacts and make the interpretation of neurogenesis
supply [9,39], whereas intracerebroventricular (i.c.v.) BrdU is prefer- studies difficult. For example, BrdU labeling is the most commonly
entially incorporated into proliferative cells in the 3V lateral wall and employed technique for assessing hypothalamic neurogenesis [7–
hypothalamic parenchyma, possibly because these cells only have 9,12,19,37–40,42,46], but the presence of incorporated BrdU mole-
access to BrdU in the CSF following i.c.v. administration [7,42]. cules within the cells may induce aberrant cellular proliferation,
Length and dosages of BrdU administration may interfere with migration, and differentiation [72,73]. In addition, genetic models
experimental observations [9,39]. For example, peripheral delivery including viral vectors, Cre recombinase, and inducible Cre-recom-
of BrdU for 15 days labels tanycytes of the median eminence and cells binase systems have been used for long-term lineage tracing of
in the hypothalamic parenchyma [39], whereas shorter periods of NPCs in the hypothalamus [9,19,39–41,46,50]. In general, genetic
administration failed to show parenchymal staining [9]. These technologies employ an endogenous promoter to drive the expres-
important factors vary considerably between studies and should be sion of a reporter gene, such as GFP or b-galactosidase, and mimic
considered when comparing experimental results. the physiological expression patterns of a relevant gene. However,
BrdU labeling of non-proliferative cells. BrdU may be incorporated discrepant expression patterns between reporter and endogenous
in apoptotic or DNA-repairing cells [68–71], leading to possible proteins [74,75] or incomplete labeling [19] have been described in
overestimation of proliferation rates in the hypothalamus (e.g., several models, raising the question on whether genetic models can
BrdU-positive neurons may be neurons undergoing apoptosis). This feasibly recapitulate endogenous neurogenesis processes. Never-
is a crucial issue for models where hypothalamic neuronal degenera- theless, genetic labeling of NPCs represents a valuable and useful
tion may be present, such as obesity [54,55]. To confirm that BrdU strategy, and the technical limitations can be minimized by careful
incorporation is due to cell proliferation, double-labeling protocols characterization of every model. For a detailed critical review about
with BrdU and proliferation markers such as Ki-67 or PCNA can be the technical limitations of methods used to study neurogenesis see
employed [33,71]. Another option is to confirm that cells marked with [71].

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

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

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In addition to hypothalamic neuronal cell loss [54,55], that progressive neurodegeneration of NPY/AgRP neurons
obesity may further exacerbate this damage by promoting in mutant mice leads to increased hypothalamic cell pro-
a reduction in the levels of neuron replacement. Indeed, liferation [8] in an effort to maintain energy-balance. If
adult hypothalamic NPCs are vulnerable to HFD-induced hypothalamic cell proliferation is blocked, the decrease in
inflammation, including IKKB/NF-kB upregulation [46]. food intake and body adiposity in these mice can be detri-
These inflammatory mediators are responsible for inhibit- mental [8].
ing the survival and proliferation of adult hypothalamic In summary, several stimuli promoting hypothalamic
NPCs and inducing neuronal differentiation deficits in cell proliferation scenarios have been identified, and in-
these cells [46]. It should be noted that selective over- clude mild neuronal cell loss and upregulation of neuro-
expression of IKKB in hypothalamic NPCs is sufficient trophic factors [7,8] (Figure 2). Notably, energy-balance
to impair neurogenesis and induce obesity in adult mice on can be re-established upon activation of hypothalamic
normal chow diet [46]. neurogenesis by these stimuli [7,8]. Therefore, we suggest
Genetic obesity is also associated with defective remo- that modulation of hypothalamic neurogenesis, and stim-
deling of feeding circuits, and obese leptin-deficient (ob/ob) ulation of a self-repair system driven by resident NPCs,
mice reveal decreased hypothalamic neurogenesis [12]. may provide potential therapies for disorders affecting the
However, it is possible that ob/ob mice exhibit fewer NPCs hypothalamus. This strategy is already being investigated
as a result of the absence of leptin, which is known to for other neurogenic regions [59]. Endogenous molecules
stimulate the proliferation of hypothalamic NPCs both in that can activate the hypothalamic neurogenic niche are
vivo and in vitro [12,16]. evident candidates for therapeutic objectives. This seems
It was recently reported that hypothalamic neurogen- to be a promising strategy because peripheral administra-
esis is reduced in aged mice [53], which is of interest tion of growth factor has been shown to repopulate the
because aging is associated with increased risk of obesity hypothalamic ARC upon acute loss of hypothalamic neu-
and neuroinflammation [57,58]. This putative link be- rons induced by glutamate insult [60]. Nevertheless, more
tween obesity, aging, and hypothalamic neurogenesis war- research is needed to fine-tune the induction of cell prolif-
rants further investigation. eration (and subsequent cell differentiation) and selective
The effects of obesity on hypothalamic neurogenesis modulation of food intake and body weight.
may be more complex because a recent investigation shows
that HFD consumption increases the neurogenic rates in Concluding remarks
the hypothalamus of adult mice, whereas selective loss of The concept of adult hypothalamic neurogenesis has chan-
the median eminence neurogenic niche protects from ex- ged the paradigm of how we understand energy-balance
cessive weight-gain upon HFD feeding [9]. In particular, regulation. It is now widely accepted that neurogenic
hypothalamic neurogenesis was increased in mice under a processes occurring in the adult rodent hypothalamus
shorter HFD period (1 month) [9]. Therefore, a possible contribute to the physiological regulation of food intake
explanation for these contradictory findings is that altera- and body weight. Mechanistically, this neuronal plasticity
tions in neurogenesis follow an activation–inhibition pat- offers the organism flexibility to respond/adapt to daily
tern, because this is known to take place for other metabolic challenges. However, the exact role of adult
hypothalamic mechanisms following HFD consumption hypothalamic neurogenesis in feeding regulation can only
[54] (Figure 2). Thus, this latter study may be reporting be clearly demonstrated after specific ablation of newly
an early compensatory activation of hypothalamic neuro- formed neurons in this region. This may be possible by
genesis promoted by mild neuronal loss – which is known using genetic strategies similar to those that revealed the
to occur upon HFD consumption [55]. This event can functional/structural importance of hippocampal neuro-
stimulate neurogenesis in the hypothalamus, as reported genesis [61,62].
in mouse models of neurodegeneration [8]. There are other relevant topics that need further inves-
Accordingly, HFD has a transient effect in hypothalamic tigation before the basis of hypothalamic neurogenesis can
cell renewal, with a proliferation peak occurring 3 days be unraveled. These include the need to clarify the origin of
after the introduction of HFD, followed by a gradual re- putative NPC subsets, to identify the endogenous factors
duction over time [6]. A possible reason for this rapid effect that promote NPC proliferation/differentiation, and to
includes direct activation of NPC division by nutritional determine the basal rates of neurogenesis in the hypothal-
cues or inflammatory mediators, which are elevated within amus.
1–3 days of HFD onset [54]. Drawing from previous work on the SVZ and SGZ
Several lines of evidence suggest that adult hypotha- [61,63], another key experiment would be to follow geneti-
lamic neurogenesis can constitute an early protective cally labeled hypothalamic NPCs from early postnatal
mechanism to preserve homeostasis under detrimental days until adulthood, and to elucidate the proliferation,
nutritional conditions (Figure 2) [6,8]. For example, block- migration, and differentiation processes of these cells.
ing cerebral cell proliferation during the initial period of However, the challenge is to find a promoter to drive
HFD-stimulated neurogenesis accelerates weight gain and transgene expression that is widely and actively expressed
obesity onset in mice [6]. Moreover, HFD regime increases in hypothalamic NPCs and that can be used as a marker in
the percentage of neurons adopting the anorexigenic genetic strategies. One candidate for such a marker is
POMC phenotype, suggesting that the maturation of neu- nestin, an intermediate filament protein often used to label
rons in feeding circuits is nutritionally regulated to pre- neural stem cells [64]; apparently, nestin is expressed in
vent further weight gain [6]. Finally, another study showed hypothalamic NPCs including tanycytes (a and b) and
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 What mechanisms are associated with the activation of endogen- hypothalamic feeding circuits. Clin. Genet. 70, 295–301
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mediating this effect? Nat. Med. 16, 403–405
 Can energy-balance be re-established upon therapeutic activation 12 McNay, D.E. et al. (2012) Remodeling of the arcuate nucleus energy-
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Acknowledgments
differentiation of hypothalamic neuroendocrine cells. Mol. Endocrinol.
We thank the FCT (Portuguese Foundation for Science and Technology),
20, 1623–1632
FEDER (Fundo Europeu de Desenvolvimento Regional), and COMPETE
27 Pelling, M. et al. (2011) Differential requirements for neurogenin 3 in
(Programa Operacional Factores de Competitividade) for financial
the development of POMC and NPY neurons in the hypothalamus. Dev.
support (SFRH/BPD/4/2011; PEst-C/SAU/LA0001/2013-2014; PTDC/
Biol. 349, 406–416
SAU-FCF/099082/2008).
28 Kruger, M. et al. (2004) NSCL-1 and NSCL-2 synergistically determine
the fate of GnRH-1 neurons and control necdin gene expression. EMBO
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