role of hypothalamic neurogenesis in feeding regulation

Role of hypothalamic neurogenesis infeeding regulationLıgia Sousa-Ferreira1, Luıs Pereira de Almeida1,2, and Claudia Cavadas1,2

1 Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-517 Coimbra, Portugal2 Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal

Review

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 recently described generation of new neurons in theadult hypothalamus, the center for energy regulation,suggests that hypothalamic neurogenesis is a crucial partof 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 onenergy-balance. This review critically discusses recentfindings 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. Understandinghow hypothalamic neurogenesis contributes to foodintake control will change the paradigm on how weperceive energy-balance regulation.

Neurogenesis in the adult brainNeurogenesis is a complex and highly regulated processthat results in the production of new neurons (seeGlossary). Neurogenesis occurs at high rates during theembryonic period when substantial quantities of new cellsare 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 indiscrete regions of the brain such as the subventricularzone (SVZ) of the lateral ventricles and the subgranularzone (SGZ) of the hippocampus [2]. NPCs from theseregions proliferate and migrate to their final destination,the olfactory bulb and the granule cell layer of the dentategyrus, respectively, where they differentiate to form newneurons and integrate into pre-existing circuits [3]. Im-portantly, neurogenesis is not simply a restorative mech-anism; it represents a functional response of the organismto daily challenges imposed by environmental and inter-nal states [2]. Moreover, the new neurons producedthrough the adult life seem to contribute to behavioralfunctions such as learning, memory consolidation, andmood regulation [3].

1043-2760/$ – see front matter

� 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2013.10.005

Corresponding author: Cavadas, C. ([email protected]).Keywords: hypothalamus; neurogenesis; neural stem cells; food intake; obesity;neuropeptide Y; proopiomelanocortin.

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

A new neural stem/progenitor cell niche has recentlybeen described to reside in the adult hypothalamus, abrain region that functions as the central regulator ofhomeostasis by controlling food intake, metabolism, and

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.

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

body temperature, among other functions. Emerging evi-dence discussed in detail below suggests that these adult-born hypothalamic neurons play a crucial role in feedingregulation, underscoring their significance in the centralcontrol of energy-balance.

Hypothalamus and feeding regulationFeeding behavior and energy-balance are regulated cen-trally by the hypothalamus. Distinct nuclei within thehypothalamus, including the arcuate nucleus (ARC), theparaventricular nucleus (PVN), the ventromedial (VMH)and dorsomedial (DMH) hypothalamus, and the lateralhypothalamic area, share neuronal interconnectionsand together they maintain body homeostasis [4]. ARCneurons produce the orexigenic neuropeptides neuropep-tide Y (NPY) and agouti-related protein (AgRP) that act toincrease food intake, and the anorexigenic neuropeptideproopiomelanocortin (POMC), the product of which (a-MSH) acts to decrease food intake [5]. The activity ofARC neurons is regulated by metabolic peripheral signalsincluding hormones and gastrointestinal peptides [4]. Forexample, the adipose-derived hormone leptin, which isproduced in proportion to body fat content, can activatethe leptin receptors present in ARC neurons [4] to increasethe expression and release of POMC and reduce the ex-pression and release of NPY, resulting in a decrease in foodintake [5]. More recently, neurogenesis has been describedin the hypothalamus and has been shown to participate inthe response of hypothalamic neuronal circuits to meta-bolic signals [6–9].

Embryonic hypothalamic neurogenesis influences adultfeeding regulationCell populations during embryonic hypothalamic

neurogenesis

The development of hypothalamic feeding circuits startsduring the embryonic period and, in rodents, continuesthrough the first 2 weeks of postnatal life [10]. Recentstudies show that hypothalamic NPCs are present in theembryonic hypothalamus; for example, in rodents, POMCand NPY neuroprecursors are identified as early as em-bryonic (E) days E10.5 and E14.5, respectively [11,12]. Inagreement, NPCs isolated from fetal rat hypothalamusexpress neuropeptides NPY, AgRP, and POMC [13]. Im-portantly, the number of immature POMC neurons in theARC triples and reaches its adult number during the fetalperiod [11]. Surprisingly, some POMC neuronal progeni-tors adopt a distinct fate, giving rise to antagonistic neu-ronal populations expressing NPY [11]. Therefore, NPYand POMC, which are expressed in mutually exclusive cellpopulations in the adult hypothalamus, colocalize in asubset of embryonic neuronal precursors [11].

Other hypothalamic cell populations are generated dur-ing the embryonic period including ependymal cells, cuboidciliated cells that line the third ventricle (3V) wall of thehypothalamus, formed at E16–E18 [14]. Tanycytes are spe-cialized ependymal cells that are located in the floor of the3V. In rodents, a subpopulation of radial glial cells (NPCs ofthe embryonic brain) initiate their differentiation into tany-cytes between E18 and the first postnatal days, and thisprocess is completed by the first month of life [14]. Tanycyte

functions are not clearly understood, but they seem to beinvolved in feeding behavior as chemosensory cells andadult NPCs that respond to diet alterations [14,15].

Impact of early nutritional and neurotrophic

environment

The nutritional and neurotrophic environment during theembryonic period, when hypothalamic NPCs are develop-ing, impacts upon the formation of an adequate NPCpopulation [16–18]. For example, offspring of dams withhigher body weight have a lower number of immatureneurons in the ARC [19]. Accordingly, proliferation ofhypothalamic NPCs in rodents during the perinatal periodis influenced by maternal diet manipulation and hormoneavailability [16–18]. Specifically, offspring subjected tonutritional restriction during the gestational period pres-ent a reduced NPC population with decreased proliferativecapacity [16]; this results in body weight and feedingdeficits in newborns that persist after weaning [18,20].By contrast, a maternal high-fat diet (HFD) regime pro-motes the proliferation, differentiation, and migration oforexigenic neuronal precursors in the hypothalamic PVNof rats, increasing the density of orexigenic neurons innewborns and leading to a higher risk of obesity [18].

A hypothesis has emerged from these findings thathypothalamic neurogenesis during the neurodevelopmentperiod 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 aconsequence, persistent changes on newborn homeostasisand, 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 keyregulators of hypothalamic neurogenesis during the embry-onic period [22–29]. For example, the proneural transcrip-tion factor Mash1 (mammalian achaete-scute homolog 1) isrequired for the generation of hypothalamic neurons, andMash1 null mice present severe hypoplasia of hypothalamicnuclei including the ARC [26]. In addition, Mash1 andneurogenin 3 (Ngn3) are involved in subtype specificationof neurons that are important for feeding regulation [26,27].Mash1 is required for the differentiation of NPY-expressingneurons and for the normal development of POMC neurons[26]. By contrast, Ngn3 inhibits the expansion of the NPYneuronal population and promotes the development ofPOMC-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 ofthese genes, TRH and CRH neuroprecursors fail to differ-entiate and produce hormones [22,24,25]. In addition, Sim1heterozygous mice have a reduced total number of PVN

81


neurons, including oxytocin neurons [30,31]. This develop-mental defect impacts upon food intake regulation becauseSim1 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 2are neuronal transcription factors that control the develop-ment of gonadotropin-releasing hormone (GnRH) neuronsin the hypothalamus [28,29]. NHLH2 and double NHLH1/2knockout mice showed dramatic loss of GnRH neurons, mostlikely due to deficient migration of neuroprogenitor cells tothe corresponding part of the hypothalamus [28,29].

Adult hypothalamic neurogenesisEmerging evidence suggests that, in addition to the SVZ andSGZ zones, active neurogenesis takes place in other regions

Box 1. Difficulties in the identification, localization, and determin

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

of the adult rodent brain [33–36]. These regions include thehypothalamus where a potential neurogenic niche has beencharacterized [8,37–40]. Some reports suggest that the basal(unstimulated) levels of neurogenesis in the hypothalamusare low [37,38,40], and are probably less than those seen inwell-established neurogenic zones [35]. However, recentpapers have reported the contrary, and have shown robustneurogenesis within the hypothalamus of mice under nor-mal conditions [12,39]. These differences may be related tothe experimental approaches used to estimate the numberof new neurons in the hypothalamus and probably to theidentification of different NPC subsets by genetic and immu-nolabeling techniques (Box 1). This is a crucial point, andreconciling these differences will need further investigation.

Nevertheless, studies in support of the existence of basalhypothalamic neurogenesis indicate that the adult rodent

ation of the proliferative capacity of hypothalamic NPCs

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].


hypothalamus contains a resident population of NPCscapable of generating new neurons [9,39–42]. In addition,proliferative NPCs have also been observed in the adulthypothalamus of other species including sheep [43], ham-ster [44], and zebrafish [45].

Importantly, recent findings indicate that the adulthypothalamic neurogenesis contributes to the regulationof food intake [7–9]. For example, most of the newbornhypothalamic progenitor cells follow a neuronal fate anddifferentiate to phenotypes important for the regulation ofappetite, including NPY/AgRP- and POMC-expressingneurons [7,8,19,37–39]. These new neurons are also re-sponsive to fasting and leptin, characteristics of functionalhypothalamic neurons [7–9,19,39].

Cellular remodeling of feeding circuits, including re-placement of mature POMC and NPY neurons, occurscontinuously during adulthood [12,46]. In young mice, halfof the NPY and POMC neurons are substituted by neuronsborn postnatally within an 8 week period [12]. However,neuronal turnover seems to slow down in adulthood[12,46]. Noteworthy, this adult neurogenesis is importantbecause it is involved in the response of energy-balancecircuits 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 partof the 3V wall, with proliferative tanycytes and prolifer-ative subependymal astrocytes [40,42], and the ventralpart of the 3V wall (median eminence), which includesproliferative tanycytes [9,39]. Moreover, evidence sug-gests that newborn neurons originating from the ventric-ular proliferative cells migrate to the hypothalamic

3V wall

3V POMC

MCH

ORX

CRHTRH

NPY/AGRPARC

LH

PVNDorsal

Medial

Ventral

Median eminence

(A)

(C)?

(B)

Figure 1. Schematic representation of the hypothalamic neurogenic niche in the adult

grey), tanycytes (blue), and subependymal cells (dark brown). There are different prolife

and proliferative subependymal astrocytes (light and dark green, respectively); and (B)

[9,42]. The ventricular neuroprogenitor cells migrate to the hypothalamic parenchyma

Proliferative cells are also present in the hypothalamic parenchyma (green) [46]; these

[50]. Hypothalamic neurons (red) express different neuropeptides important for the regu

are not represented. Abbreviations: AgRP, agouti-related protein; ARC, arcuate nucleus

concentrating hormone; NPY, neuropeptide Y; ORX, orexin; POMC, proopiomelanoco

ventricle.

parenchyma where they are incorporated into the appetitecircuits [19,39,41] (Figure 1).

Tanycytes are considered to be adult hypothalamicNPCs in view of their proliferative capacity both in basaland 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 thelateral 3V wall) and b-tanycytes (in the median eminence)[14,40]. Astrocytes in the subependymal layers are alsoregarded as possible adult hypothalamic NPCs becausethey share common features with neural stem cells fromthe SVZ [47], including subependymal localization, stain-ing for glia-specific markers, and increased proliferationupon growth factor stimulation [42].

The shape and location of proliferative hypothalamicNPCs (tanycytes and subependymal astrocytes) placesthem 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 bythe bloodstream such as glucose and hormones [14]. More-over, tanycyte cell bodies that line the lateral wall of the 3Vand subependymal astrocytes, via a cellular process thatprotrude the ependymal cell layer, are in contact with thecerebrospinal fluid (CSF) and molecules present in thisfluid [14,42]. In addition, tanycytes have a long basalprocess that penetrates into the hypothalamic parenchymaand allows close proximity to energy-sensing neurons [14].

The proximity of hypothalamic NPCs to nutritional cuesis an important factor supporting the putative role of neu-rogenesis in feeding regulation because NPC proliferationand differentiation to neuronal phenotypes could then becontrolled by cues that signal the metabolic needs of theorganism. Indeed, several lines of evidence indicate thathypothalamic NPCs can sense and respond to peripheral

TanycyteKey:

Prolifera�ve tanycyte

Prolifera�ve subependymal astrocyte

Prolifera�ve cell in the hypothalamicparenchyma

Hypothalamic neuron

Migra�on Integra�on

Subependymal cell

Ependymal cell

TRENDS in Endocrinology & Metabolism

rodent brain. The third ventricle (3V) wall is constituted by ependymal cells (light

rative zones on the 3V wall: (A) the medial part, containing proliferative tanycytes

the ventral part (median eminence), containing proliferative tanycytes (light green)

(green arrow) and are incorporated in the appetite circuits (red arrows) [41]. (C)

cells may represent a cellular subtype generated from ventricular progenitor cells

lation of feeding and are located in hypothalamic nuclei (grey). Cellular processes

; CRH, corticotropin-releasing hormone; LH, lateral hypothalamus; MCH, melanin

rtin; PVN, paraventricular nucleus; TRH, thyrotropin-releasing hormone; 3V, third

83


nutritional signals [9,12,46,48,49]. For example, tanycyteshave chemosensory properties for glucose, hormones, andneurotrophic factors that activate intracellular pathways[48,49]. In addition, energy-balance alterations, such asHFD 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 notfully validated but represents an emerging area of investi-gation.

There is no consensus about the identity of adulthypothalamic NPCs. For example, a recent report iden-tifies the ventral b-tanycytes as hypothalamic NPCs be-cause they proliferate in basal conditions and theirneuronal descendants populate the hypothalamus ofyoung adult mice [9,39]. However, another study showedthat lateral a-tanycytes are the key components of thisneurogenic niche [40]. Moreover, each of these two reportsexcluded the other tanycyte subtype as potential hypo-thalamic NPCs [39,40]. Interestingly, although both stud-ies are based on mouse models with tanycyte-specific Crerecombinase expression, the different promoters drivingCre expression were specific for different tanycyte sub-populations, and this may account for the conflictingresults [39,40]. Another possibility is that a- and b-tany-cytes represent functionally distinct NPC subsets, orpossibly NPCs in sequential differentiation states, be-cause a-tanycytes can give rise to more ventrally locatedb-tanycytes [40].

The hypothalamic parenchyma may also harbor divid-ing NPCs because proliferating cell ‘pairs’ were observedinteriorly to the ventricular zones [8,37–39] (Figure 1).Furthermore, studies based on the stem cell marker SOX2revealed a significant number of NPCs within the mousehypothalamic parenchyma under normal conditions[39,46]. Parenchymal proliferative cells may arise fromthe 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 todivide within the hypothalamic parenchyma [39]. Howev-er, because the cellular origin of most parenchymal prolif-erative cells is still unknown this hypothesis requiresfurther investigation. In addition, BrdU (bromodeoxyur-idine, a thymidine analog that is selectively incorporatedby dividing cells) injected into the 3 V labels a greaternumber of cells in the hypothalamic parenchyma than inthe 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 suggestthat hypothalamic parenchymal NPCs have a shorter cellcycle 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 bederived from the ventricular zone) which, because of theirlocation, can respond more rapidly to metabolic signals byproliferating and differentiating to new neurons withinthe hypothalamus.

In summary, although several studies have reportedon the identity, location, and proliferative capacity of

84

hypothalamic NPCs [9,38–40,42,46], the often conflictingfindings warrant further investigation.

Adult hypothalamic neurogenesis and the role of neural

growth factors

In rodents, neurogenesis in the adult hypothalamus isenhanced by intraventricular administration of neuralgrowth factors (Table 1); these factors drive a higherpercentage of cells towards the neuronal phenotype com-pared to endogenous neurogenesis [7,37,42]. Moreover, theidentity of proliferative hypothalamic cells as newbornneurons 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 promoteslong-term weight loss is by enhancing hypothalamic neu-rogenesis [7]. Inhibition of cell proliferation in the ventralregions 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 thehypothalamic 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 neurotrophicfactor (BDNF) or insulin-like growth factor 1 (IGF-1)(growth factors that are also expressed endogenously inthe hypothalamus, as well as their receptors), activatesthe production of new neurons in this region [7,37,42].Moreover, GnRH, which is expressed by hypothalamicneurons, can promote the proliferation and survival ofNPCs in the hypothalamus of aged mice [53]. Thus, neu-rogenesis activation by endogenous molecules may consti-tute a physiological mechanism to respond to metabolicchallenges, helping to modulate feeding circuits appropri-ately throughout adult life. However, it remains unclearif metabolic cues, such as moderate disturbances inenergy-balance, can trigger a compensatory upregulationof neurotrophic factors (or other molecules) in thehypothalamus.

Interestingly, growth factors induce different levels ofneurogenesis in different hypothalamic nuclei [8,37,42].For example, IGF-1 administration induces neurogenesisin the medial periventricular and parenchymal zones [42]and BDNF infusion leads to high density of new cells in thePVN [37]. Finally, degeneration of AgRP neurons increasescell proliferation exclusively in the ARC [8]. Collectively,these observations highlight a pattern of region-specificactivation of hypothalamic neurogenesis which might beinfluenced by the energy status of the organism.

Impact of energy-balance disorders on adult

hypothalamic neurogenesis

Neurogenesis in the adult hypothalamus is modulated bycellular dysfunction such as neuronal cell loss, obesity-induced inflammation, and neurodegeneration [6,8,12,46].Obesity and HFD induce hypothalamic injuries in rodentsand humans, including activation of inflammatory andendoplasmic reticulum stress pathways, microglia and

Table 1. Activation of adult hypothalamic neurogenesis by growth factors and correlation with receptors in rodentsa

Stimulus Administration Hypothalamic neurogenesis Localization of prolifer-

ative cells

Correlation with receptors Refs

BDNF I.c.v. infusion

for 12 days

Increases cell proliferation (BrdU+ cells)

A significant percentage of new cells are

neurons

More new neurons in the PVN than in the

SVZ

Diffusely in the

hypothalamus

parenchyma

High density in the PVN

Newborn cells do not

express BDNF receptor

Localization of newborn

cells and BDNF receptors

correlate strongly

[37]

CNTF I.c.v. infusion

for 7 days



neurons (including NPY and POMC

neurons)

Some new cells are oligodendrocytes

Diffusely in the

hypothalamus

parenchyma

High density in the ARC

and median eminence

Some newborn cells

express CNTF receptor


cells and CNTF receptors

correlate strongly

[7]

IGF-1 I.c.v. infusion

for 7 days



neurons

High density in the

hypothalamus

parenchyma and in the

caudal periventricular

zone

Some newborn cells

express IGF-1 receptor in

the periventricular zone


cells and IGF-1 receptors

correlate strongly

[42]

FGF, EGF, and

FGF+EGF

Single injection

directly into

the 3V

Increases cell proliferation (BrdU+ and

nestin+ cells)

FGF is more potent in inducing

hypothalamic neurogenesis

Newborn cells are astrocytes and neurons

(including orexin-A neurons)

3V wall (2–3 cell layers in

the ependymal layer)

FGF receptors are

expressed in the cells of

the 3V wall

[41]

EGF+FGF Subcutaneous

injection for

10 days


Promotes hypothalamic neuronal

repopulation upon acute toxic effect of

glutamate

ARC parenchyma N/A [60]

FGF I.c.v. infusion

for 7 days


Newborn cells are vimentin+ tanycytes (in

the 3V wall)

In the medial part of the 3V

wall

Sub/periventricular zone

FGF-10 and FGF-18 are

expressed within tanycyte-

containing regions

[40]

aAbbreviations: 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]. Itwas recently shown that obesity also inhibits adult hypo-thalamic neurogenesis (Figure 2), resulting in reducedgeneration of new neurons, including NPY and POMCneurons, in addition to decreased proliferative capacityof hypothalamic NPCs [12,46]. Further, a HFD regime

(A)Physiologicalresponse

• Mild neuronal loss

Energy

Endogenous hypoth

S�mulus:• Growth factors

Ac�va�on

Homeostasis

Figure 2. Endogenous hypothalamic neurogenesis contributes to the regulation of ener

neuronal loss to re-establish homeostasis as a physiological response [7,8]. (B) Hyp

inflammation, contributing to a defective energy-balance in pathological conditions [12

in mice restrains the constitutive self-renewal capacityof NPY and POMC neurons by promoting the retentionof old neurons and the apoptosis of newborn neurons [12].Conversely caloric restriction has the opposite effect and isable to reverse the reduction in hypothalamic neurogenesisin obese mice [12].

(B)Pathology

• Severe neuronal loss• Obesity-induced inflamma�on

balance

alamic neurogenesis

Inhibi�on

Defec�ve

TRENDS in Endocrinology & Metabolism

gy-balance. (A) Hypothalamic neurogenesis is stimulated by growth factors or mild

othalamic neurogenesis is inhibited by severe neuronal loss or obesity-induced

,46].

85


In addition to hypothalamic neuronal cell loss [54,55],obesity may further exacerbate this damage by promotinga reduction in the levels of neuron replacement. Indeed,adult hypothalamic NPCs are vulnerable to HFD-inducedinflammation, including IKKB/NF-kB upregulation [46].These inflammatory mediators are responsible for inhibit-ing the survival and proliferation of adult hypothalamicNPCs and inducing neuronal differentiation deficits inthese cells [46]. It should be noted that selective over-expression of IKKB in hypothalamic NPCs is sufficientto impair neurogenesis and induce obesity in adult mice onnormal 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 NPCsas a result of the absence of leptin, which is known tostimulate the proliferation of hypothalamic NPCs both invivo and in vitro [12,16].

It was recently reported that hypothalamic neurogen-esis is reduced in aged mice [53], which is of interestbecause aging is associated with increased risk of obesityand neuroinflammation [57,58]. This putative link be-tween obesity, aging, and hypothalamic neurogenesis war-rants further investigation.

The effects of obesity on hypothalamic neurogenesismay be more complex because a recent investigation showsthat HFD consumption increases the neurogenic rates inthe hypothalamus of adult mice, whereas selective loss ofthe median eminence neurogenic niche protects from ex-cessive weight-gain upon HFD feeding [9]. In particular,hypothalamic neurogenesis was increased in mice under ashorter HFD period (1 month) [9]. Therefore, a possibleexplanation for these contradictory findings is that altera-tions in neurogenesis follow an activation–inhibition pat-tern, because this is known to take place for otherhypothalamic mechanisms following HFD consumption[54] (Figure 2). Thus, this latter study may be reportingan early compensatory activation of hypothalamic neuro-genesis promoted by mild neuronal loss – which is knownto occur upon HFD consumption [55]. This event canstimulate neurogenesis in the hypothalamus, as reportedin mouse models of neurodegeneration [8].

Accordingly, HFD has a transient effect in hypothalamiccell renewal, with a proliferation peak occurring 3 daysafter the introduction of HFD, followed by a gradual re-duction over time [6]. A possible reason for this rapid effectincludes direct activation of NPC division by nutritionalcues or inflammatory mediators, which are elevated within1–3 days of HFD onset [54].

Several lines of evidence suggest that adult hypotha-lamic neurogenesis can constitute an early protectivemechanism to preserve homeostasis under detrimentalnutritional conditions (Figure 2) [6,8]. For example, block-ing cerebral cell proliferation during the initial period ofHFD-stimulated neurogenesis accelerates weight gain andobesity onset in mice [6]. Moreover, HFD regime increasesthe percentage of neurons adopting the anorexigenicPOMC 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

that progressive neurodegeneration of NPY/AgRP neuronsin mutant mice leads to increased hypothalamic cell pro-liferation [8] in an effort to maintain energy-balance. Ifhypothalamic cell proliferation is blocked, the decrease infood intake and body adiposity in these mice can be detri-mental [8].

In summary, several stimuli promoting hypothalamiccell proliferation scenarios have been identified, and in-clude mild neuronal cell loss and upregulation of neuro-trophic factors [7,8] (Figure 2). Notably, energy-balancecan be re-established upon activation of hypothalamicneurogenesis by these stimuli [7,8]. Therefore, we suggestthat modulation of hypothalamic neurogenesis, and stim-ulation of a self-repair system driven by resident NPCs,may provide potential therapies for disorders affecting thehypothalamus. This strategy is already being investigatedfor other neurogenic regions [59]. Endogenous moleculesthat can activate the hypothalamic neurogenic niche areevident candidates for therapeutic objectives. This seemsto be a promising strategy because peripheral administra-tion of growth factor has been shown to repopulate thehypothalamic ARC upon acute loss of hypothalamic neu-rons induced by glutamate insult [60]. Nevertheless, moreresearch is needed to fine-tune the induction of cell prolif-eration (and subsequent cell differentiation) and selectivemodulation of food intake and body weight.

Concluding remarksThe concept of adult hypothalamic neurogenesis has chan-ged the paradigm of how we understand energy-balanceregulation. It is now widely accepted that neurogenicprocesses occurring in the adult rodent hypothalamuscontribute to the physiological regulation of food intakeand body weight. Mechanistically, this neuronal plasticityoffers the organism flexibility to respond/adapt to dailymetabolic challenges. However, the exact role of adulthypothalamic neurogenesis in feeding regulation can onlybe clearly demonstrated after specific ablation of newlyformed neurons in this region. This may be possible byusing genetic strategies similar to those that revealed thefunctional/structural importance of hippocampal neuro-genesis [61,62].

There are other relevant topics that need further inves-tigation before the basis of hypothalamic neurogenesis canbe unraveled. These include the need to clarify the origin ofputative NPC subsets, to identify the endogenous factorsthat promote NPC proliferation/differentiation, and todetermine 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 postnataldays until adulthood, and to elucidate the proliferation,migration, and differentiation processes of these cells.However, the challenge is to find a promoter to drivetransgene expression that is widely and actively expressedin hypothalamic NPCs and that can be used as a marker ingenetic strategies. One candidate for such a marker isnestin, an intermediate filament protein often used to labelneural stem cells [64]; apparently, nestin is expressed inhypothalamic NPCs including tanycytes (a and b) and

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 adiscordant 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 zonesmay exist within the hypothalamus; careful design offuture studies will be necessary to obtain new reliableinformation about the hypothalamic neurogenic nicheand to reconcile existing contradictory findings.

Another important consideration is that the currentstudies were based solely on rodent models, and the rele-vance of key observations for human physiology needs to beestablished. Although many crucial questions remain un-answered (Box 2), the idea of exploiting hypothalamicneurogenesis therapeutically for diseases such as obesityis innovative and exciting.

AcknowledgmentsWe thank the FCT (Portuguese Foundation for Science and Technology),FEDER (Fundo Europeu de Desenvolvimento Regional), and COMPETE(Programa Operacional Factores de Competitividade) for financialsupport (SFRH/BPD/4/2011; PEst-C/SAU/LA0001/2013-2014; PTDC/SAU-FCF/099082/2008).

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