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m c evans and g m anderson Nutritional regulation 58: 2 R107–R128 Review of reproduction

Neuroendocrine integration of nutritional signals on reproduction

Correspondence Maggie C Evans and Greg M Anderson should be addressed to M C Evans Centre for Neuroendocrinology and Department of Anatomy, University of Otago School of Email Medical Sciences, Dunedin, New Zealand maggie.evans@anatomy. otago.ac.nz

Abstract

Reproductive function in mammals is energetically costly and therefore tightly regulated Key Words by nutritional status. To enable this integration of metabolic and reproductive function, ff insulin information regarding peripheral nutritional status must be relayed centrally to the ff leptin gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. ff ghrelin The metabolically relevant hormones leptin, insulin and ghrelin have been identified ff GNRH as key mediators of this ‘metabolic control of fertility’. However, the neural circuitry ff fertility through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone–neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction

Journal of Molecular Endocrinology is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone–neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good

strategy for identifying whether a targeted pathway is absolutely required, critically Journal of Molecular involved, sufficient or dispensable in the metabolic control of fertility. Endocrinology (2017) 58, R107–R128

Introduction

Mammals, particularly females, must invest an enormous receive and integrate information about peripheral amount of energy into conceiving, carrying and rearing metabolic status. Indeed, each level of the HPG axis has their progeny to preserve their genetic lineage. Therefore, the capacity to respond to changing levels of nutritional to ensure adequate energy is available to support the cues (Comninos et al. 2014). However, the gonadotropin- high demands of pregnancy and successful weaning releasing hormone (GNRH) neurons residing in the of offspring, reproductive function tends to become hypothalamus are the primary drivers of reproductive suppressed during times of low-energy availability. For function, and impaired GNRH signaling is considered this coordinated regulation of energy homeostasis and the underlying cause of reproductive suppression due to fertility to occur, the hypothalamic–pituitary–gonadal nutritional stress. (HPG) axis governing reproductive function must

10.1530/JME-16-0212 Journal of Molecular Endocrinology safeguard reproductive function and thus species’ survival. safeguard reproductive function and thus species’ survival. the complexityandinherent redundanciesbuiltinto relayed centrallytotheGNRH neuronsandalsohighlights important insightintohow peripheral metabolicstatusis mechanisms underlying nutritional infertility provides in isolation genetic deficiencies,asnosinglepathwayiseveroperating meaningful approach,exceptperhapsincasesofspecific and is arguably not anexperimentallyandphysiologically exerts itsimpactonGNRHreleaseprovesextremelydifficult the specific pathways bywhicheachfactorindependently due totheneteffectofallthese.Trying todisentangle suppression of the reproductive neuroendocrine axis is response) isinitiated,anditseemslikelytheconsequent (as wellasactivationofthestressaxesandcounter-regulatory multitude ofgut-andadipose-derivedhormoneresponses or chronicunder-nutrition,aseriesofeventsinvolving function isextensive. from thesesignalsandthengoontomodulateHPGaxis extra-hypothalamic) circuitry abletoreceiveinformation energy statuscentrallybutalsothehypothalamic(and nutritional signalsrelayinginformationaboutperipheral challenging areaofresearch. Notonlyaretherenumerous and nutritionalsignalsinvolvedremainsanactive hypothalamus, unraveling the specific neuralsubstrates reproductive functionisknowntooccurprimarilyinthe 2003 availability appearstobenonlinear( 2007 related totheseverityofenergeticstress( Furthermore, thesuppressionofGNRH/LHpulsatilityis Nosbisch 1991 to immediatechangesinenergyavailability( from long-term changes in adiposity and is largely due function duetonutritionalstresscanoccurindependently 2011 unquestionably associatedwithinfertility( 2005 hypogonadism ( the gonadotropins,ultimatelyresultinginhypothalamic secretionof suppressed, whichinturnreducespituitary periods ofenergeticstress,GNRHpulsesbecome & Moenter2010 which thengoontodrivegonadalfunction( hormone (LH) and follicle-stimulating hormone (FSH)) stimulates thereleaseofgonadotropins(luteinizing glandwhereit and travelstotheanteriorpituitary pulsatile mannerintothehypophysealportalcirculation DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Review In response to an energetic stress, such as an acute fast In responsetoanenergeticstress,suchasacutefast Under normalconditions,GNRHissecretedina ). Althoughthisdelicatecontrolofmetabolicand ); yet,thedependenceofLHpulsatilityonenergy ), suppressionofneuroendocrinereproductive , Huang in vivo t al et , Compagnucci Loucks , . Nevertheless, identifying the discrete . Nevertheless,identifyingthediscrete . 2008 Herbison 2016 et al ). Althoughhuman obesity is . 1998 et al m

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Christian anderson t al et et al et al ). . . . reduced levelsofplasmaglucose,suppressedthyroid limited to)alteredlevelsofgutandadiposehormones, endocrine-metabolic aberrations, including (but not hypothalamic amenorrhea(FHA))exhibitarangeof presenting withnutritionalinfertility(i.e.functional of reproductive function is challenging. Clinically, women specific componentscriticallyinvolvedinthesuppression nutritional stressismultifaceted,soidentifyingthe As mentionedpreviously, thebody’s responseto Identifying thekey players normal metaboliccontroloffertility. for, criticallyinvolvedinand/orsufficienttopermitthe of whetheridentifiedpathwaysareabsolutelyrequired inherent redundanciesofthesystemthroughdiscussions modulate reproduction,whilealsoemphasizingthe neuroendocrine pathwayswherebynutritionalsignals This reviewwillattempttohighlightsomeofthekey to nutritionalstress.For example,preventingthe is thoughttomediatereproductive suppressiondue in response to complete fasting ( in responsetochanges fatmass,butfallrapidly leptin concentrationschangegraduallyovertime feeding andincreaseenergyexpenditure.Serum sufficiency andacts onthe hypothalamus tosuppress to bodyfatness,andsignalsenergy proportion in is secreted fromadipocytesintothebloodstream appears tobeaparticularlyimportantfactor. Leptin chronically elevatedcortisolconcentrations( function, alteredgrowthhormonesecretionpatternsand Chan Leptin, thehormoneproductofobesitygene( Leptin energy availability. axes activationinreproductivesuppressionduetolow function andwillalsobrieflytouchupontheroleofstress whereby these key nutritional factors influence HPG review will therefore focus on the discrete mechanisms that inatleastsomecasestheireffectsareadditive.This GNRH/LH pulsatility(andthusfertility)thanothersand insulin andghrelin,exertamorecriticalinfluenceover studies thatcertainnutritionalsignals,suchasleptin, reproductive axis,weknowfrombothanimalandclinical factors independentlysuppressestheneuroendocrine 2011 & Warren 2006 1989 of reproduction Nutritional regulation Published byBioscientifica Ltd. ). Although it remains a possibility that each of these , t al et Laughlin &Yen 1997 . 2003 , ), and this fall in leptin concentration Scheid &DeSouza2010

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Review m c evans and g m anderson Nutritional regulation 58:2 R109 of reproduction

starvation-induced fall in leptin with exogenous leptin was associated with elevated LH pulsatility and polycystic shown to prevent the starvation-induced delay in ovulation ovary syndrome (PCOS) (Laughlin et al. 1997), and insulin- in female mice (Ahima et al. 1996). Accordingly, women sensitizing drugs (e.g. metformin) have successfully with infertility due to a negative energy balance exhibit been used to induce ovulation and treat some of the reduced circulating leptin concentrations (Laughlin & Yen pathophysiological features associated with PCOS (Katsiki 1997, Corr et al. 2011), and administration of recombinant & Hatzitolios 2010). Encouragingly, animal studies human leptin to these women not only increased their LH support these clinical findings. For example, lean and pulsatility and restored ovulation but also improved their normoglycemic female mice exhibiting varying degrees thyroid and growth hormone axes, independent from of insulin resistance and hyperinsulinemia were shown dietary changes or weight gain (Welt et al. 2004). These to have subtle alterations in their HPG axis and also had data suggest that an acute decrease in circulating leptin polyovular follicles (Nandi et al. 2010). Although insulin plays a key role in mediating the effects of low energy can act both peripherally and centrally to modulate HPG availability on reproductive function. axis function, we know that insulin’s central actions play In further support of leptin’s role in the metabolic a role in mediating many of its reproductive effects as regulation of fertility, humans and mice with a congenital mice exhibiting brain-specific deletion of insulin receptors leptin deficiency (ob/ob), as well as leptin receptor (LepR)- (InsR) exhibit subfertility due to mild hypothalamic deficient db/db( ) mice, are infertile and obese despite being hypogonadism (Bruning et al. 2000). However, in contrast energy replete, and leptin treatment is sufficient to restore to these brain-specific InsR-knockout mice, our group body weight control and reproductive function in leptin- recently demonstrated that mice exhibiting forebrain deficient individuals (Ingalls et al. 1950, Hummel et al. neuron-specific deletion of InsR displayed normal HPG 1966, Barash et al. 1996, Chehab et al. 1997, Mounzih et al. axis function (Evans et al. 2015), which challenges the 1997, Farooqi et al. 1999, 2002). Like the global LepR- hypothesis that neuronal insulin signaling is required. deficient mice, mice exhibiting forebrain neuron-specific Nevertheless, many findings implicate abnormal insulin deletion of LepR are also infertile and obese, highlighting signaling in the pathogenesis of reproductive dysfunction. that leptin’s central actions, vs peripheral actions, are However, in contrast to leptin, central insulin signaling is critically involved in regulating body weight homeostasis not absolutely required for fertility. and fertility (Quennell et al. 2009). Lastly, central leptin immune neutralization using leptin antiserum caused Ghrelin a reduction in LH pulsatility in rats (Carro et al. 1997).

Journal of Molecular Endocrinology These findings, among others, convincingly demonstrate Unlike the anorexigenic peptides insulin and leptin, that leptin plays an important physiological role in the which promote GNRH/LH pulsatility and reproductive regulation of metabolic and reproductive function. function, the orexigenic peptide ghrelin has been shown to consistently suppress GNRH pulsatility and gonadotropin release (Furuta et al. 2001, Kluge et al. Insulin 2007, 2009, 2012, 2013, Kluge 2012). Although ghrelin The pancreatic peptide hormone insulin (best known for is predominantly produced in the stomach, ghrelin- regulating glucose homeostasis and body weight regulation expressing neurons have also been identified in the (Belgardt & Bruning 2010)) has also emerged as a key hypothalamus (Cowley et al. 2003), yet it remains unclear modulator of reproductive function. Clinically, diabetic whether the actions of brain-derived ghrelin are the same insulin insufficiency (i.e. type 1 diabetes) in humans is as those for circulating ghrelin. Under normal conditions, associated with delayed puberty, reduced LH pulsatility and circulating ghrelin exhibits a circadian pattern whereby hypothalamic hypogonadism, despite sufficient energy its concentration becomes elevated in anticipation of availability; yet, improved insulin therapy has ameliorated meals. However, in women exhibiting chronic under- many of these issues (Codner et al. 2012). Additionally, nutrition, chronically elevated basal ghrelin levels are reduced insulin levels, presumably due to energy deficiency, observed and are correlated with suppressed reproductive are likewise associated with suppression of neuroendocrine function (Scheid & De Souza 2010). Ghrelin deficiency, reproductive function in women with FHA (Laughlin on the other hand, does not significantly affect fertility & Yen 1997), which further suggests insulin promotes or feeding behavior in mice (Sun et al. 2003). The latter GNRH/LH secretion. Conversely, hyperinsulinemia observation is likely due to the fact that the ghrelin and/or insulin resistance (i.e. type 2 diabetes), are often receptor (the growth hormone secretagogue receptor

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0212 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:55:05PM via free access Journal of Molecular Endocrinology However, therolesofthesemetabolic hormonesin effect ontheHPGaxis( inhibitory fertility andhasbeenshown to haveapredominantly adipocytes, is alsoimplicated inthemetabolic control of 2006 ( and appear to facilitate GNRH release and HPG function peptide YY3-36(PYY)arebothstimulatedbyfoodintake anorectic gut peptides glucagon-like peptide (GLP)-1 and and coworkers ( HPG axisfunction,asthoroughlyreviewedbyComninos are manyothernutritionalfactorsthatalsoinfluence relayed totheneuroendocrinereproductiveaxis,there major signalswherebyperipheral metabolic statusis Although leptin,insulinandghrelinappeartobethe Other nutritionalsignals suppresses theneuroendocrinereproductiveaxis. player inthemechanismwherebylowenergyavailability 2005 reduced leptin-inducedinhibitionofghrelin( Warren 2006 exhibit chronicallyelevatedghrelinlevels( and womenwithdisorderedeatingamenorrheaalso in theirnormallycyclingpeers( that areapproximately85%greaterthanthoseobserved women withamenorrheaexhibitplasmaghrelinlevels deficient mice( signaling improvesthereproductivephenotypeofleptin- on fertility. Insupportofthis,inhibitionghrelin leptin’s andinsulin’s effects, thereby acting as a‘brake’ accompanies nutritionalstressisthoughttoantagonize the increaseincirculating ghrelinconcentrationsthat Nevertheless, undernormalphysiologicalconditions, reproductive parameterswerenotassessedinthesemice. likely duetocompensationbyotherfactors.Unfortunately, mice, butfailedtocauselong-termimpacts( caused anacuteincreaseinfoodintakeandbodyweight induced reductioninLHsecretion. ghrelin-knockout mice were protected against a fasting- have beenmoreinformativetodeterminewhetherthe knockout miceisperhapsnotsurprising.Itwouldarguably intheghrelin- the lackoffertilityphenotypeobserved Considering ghrelin’s actionsonGNRHrelease, inhibitory of ghrelinpeptide, ghrelin signaling is not abolished. 2003 type 1a(GHSR1a))has constitutive activity( Beak DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Review Chronic overexpression of ghrelin, on the other hand, ). Thesestudiesstronglyimplicateghrelinasakey ). Adiponectin, a protein hormone secreted by white , t al et Holst &Schwartz2004 . 1998 , Schneider Zhu Comninos , et al MacLusky et al . 2013 et al . 2008 t al et ), soevenintheabsence ). Furthermore,exercising . 2014 m

. 2000 evans Klenke ). For example, the and Printed inGreatBritain , Qi t al et t al et Pinilla Schneider & g et al

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anderson . 2004 . 2014 . 2015 t al et t al et et al ), ). ), . . . peripheral signalsofnutritionalstatus( influence ofleptin,insulinandghrelin,aswellother is primarilythroughthisspecializednetworkthatthe neurons (termedtheGNRHneuronalnetwork)andit regulated by a network of hormone-sensitive afferent of theneuroendocrinereproductiveaxis,theyareinturn asthefinalgatekeepers Although GNRHneuronsserve The GNRHneuronal network as influentialthoseofleptin,insulinandghrelin. conveying nutritionalstatuscentrallydonotappeartobe as wellglucose( ( some nutritional signals, including insulin and ghrelin reproductive axis. 2014 it appears information regarding peripheral energy status processers andintegratorsof individualnutritionalsignals, fail-safe. InsteadofGNRHneurons actingasthereceivers, metabolic controloffertility tobemorefine-tunedand seem redundant and inefficient, itprobably allowsthe reproduction largelyoccursupstreamofGNRHneurons. the neuroendocrineintegrationofnutritionalsignalson ( hypothalamic circuitry afferenttoGNRHneurons its neuroendocrineeffectsappeartobemediatedthrough in brainslicepreparations( although it can modulate GNRH neurons directly, at least role inobesity-relatedinfertility. With regardtoghrelin, suggesting directinsulin–GNRHsignalingmayplaya 2007 from high-fatdiet-inducedinfertility( Interestingly, however, GNRH-IRKOmicewereprotected 2009 IRKO mice) ( respectively, GNRH-specificdeletionofInsR(GNRH- of LepR( ( although miceexhibitingbrain-specificdeletionofInsR regulation offertilitybynutritionalfactors.Forexample, does notplayacriticalrolewhenitcomestothe in mostcases,directhormone–GNRHcommunication effects thanatthelevelofindividualafferentneurons, the GNRHneuronalnetworkwouldhavemoreprofound regulation attheleveloffinalcommonoutput it mightbespeculatedthatdisruptionofmetabolic of reproduction Nutritional regulation Farkas Forbes Bruning Published byBioscientifica Ltd. Indeed, GNRHneuronsthemselves Although thisindirectmechanismofactionmay ), appearstoconvergeontheneuroendocrine ) and adiponectin ( ) didnotresultinanyreproductiveperturbations. et al et al Quennell et al . 2013 . 2009 Divall . 2000 , , et al t al et Evans ) orforebrainneuron-specificdeletion Zhang Schaeffer

. 2009 . 2010 Downloaded fromBioscientifica.com at09/24/202102:55:05PM et al Klenke et al ) weresubfertileandinfertile, Farkas et al . 2014 ) or LepR ( . 2007 . 2013 t al et t al et a , ), PYY( 58 . 2014 DiVall DiVall can . 2013 ). It thus appears : 2 Comninos Quennell directlydetect et al Pinilla ). Although et al ), manyof . 2015 . 2015 R110 et al t al et t al et via freeaccess ), ), . . . Review m c evans and g m anderson Nutritional regulation 58:2 R111 of reproduction

is first channeled through upstream circuitry. Information concentration within the GNRH neuron (Herbison & encoded by individual nutritional signals thus becomes Moenter 2011). contextualized among the information encoded by the To investigate the role(s) of leptin and insulin others, yielding a comprehensive snapshot of peripheral signaling via GABAergic neurons in the control of energy status. The GNRH neurons then receive this HPG axis function, our lab generated mice exhibiting integrated information and can respond accordingly, GABA-specific deletion of LepR Zuure( et al. 2013) and thereby maintaining their role as the final gatekeepers of InsR (Evans et al. 2014b) and demonstrated that leptin reproductive function. signaling, but not insulin signaling, via GABAergic Characterizing the neuropeptide and/or neurons is a major component of the circuitry neurotransmitter identities of this ‘fuel-gauging’ network whereby peripheral metabolic status is relayed to the subserving GNRH neurons, as well as their role in neuroendocrine reproductive and metabolic axes. Mice mediating the metabolic control of fertility, remains lacking LepR from GABA neurons were profoundly an active area of research. Although many questions obese and exhibited delayed puberty and subfertility remain unanswered, a lot of headway has been made (Zuure et al. 2013), whereas mice lacking InsR from (Table 1). Perhaps not surprisingly, many of the same GABA neurons exhibited a very mild metabolic neuronal populations previously identified to play a role phenotype and normal pubertal development and in energy balance homeostasis have now been identified fertility (Evans et al. 2014b). Although it remains a to play a role in modulating reproductive function as possibility that the reproductive impairments observed well. Conversely, many neuronal populations previously in the GABA-specific LepR-knockout mice were directly known to modulate GNRH release are now recognized as related to their obesity phenotype, our lab and others integrators of nutritional information. have demonstrated that reproductive competency can be maintained despite profound obesity (Bates et al. 2003, Singireddy et al. 2013), suggesting leptin–GABA GABA-expressing neurons signaling is directly involved in the control of HPG axis While emphasis is often placed on the role of neuropeptide- function. In contrast, insulin–GABA signaling does not expressing populations with regard to the integration of appear to be critically involved in regulating fertility. metabolic and reproductive status, the contribution of Although leptin signaling via GABAergic neurons neurotransmitters also deserves attention. It has been appears to play a critical role in the regulation of fertility, known since the 1980s that gamma-amino butyric many GABAergic neurons co-express other transmitters

Journal of Molecular Endocrinology acid (GABA) (the main inhibitory neurotransmitter in (Table 2), including NPY and AgRP (Meister 2007), the mammalian central nervous system) is involved in kisspeptin (Cheong et al. 2015) and dopamine (Olson & the regulation of GNRH release both before and after Nestler 2007, Marshall et al. 2016), for example, and it is puberty (Adler & Crowley 1986, Nikolarakis et al. 1988, therefore possible that both the neuropeptide(s) and/or Donoso et al. 1994, Mitsushima et al. 1994), and that neurotransmitter(s) released from these neurons act as GABAergic afferents compose a major group of synaptic the effectors on GNRH neurons. At this stage, it is not inputs to GNRH neurons. Similarly, it has been known clear whether leptin signaling via GABAergic neurons for some time that GABAergic neurons are modulated critically regulates fertility by modulating GABA release by nutritional factors, including leptin (Ovesjo et al. or the release of other transmitters, or both. However, 2001). However, it was not until Sullivan and coworkers evidence for the latter is strong. Furthermore, although demonstrated that GABAergic neurons play a role in insulin signaling via GABAergic neurons themselves conveying metabolic information to GNRH neurons does not appear to play a critical role (Evans et al. (Sullivan et al. 2003, Sullivan & Moenter 2004) that 2014b), insulin was shown to increase the number of

the role of GABAergic neurons in the integration of synaptic GABAA receptors to postsynaptic domains, nutritional and reproductive status became appreciated. which is the limiting factor in eliciting a greater

Indeed, the GNRH neurons express both GABAA and synaptic response (Wan et al. 1997, Bell-Horner et al.

GABAB receptor isoforms. Binding of GABA to the GABAB 2006). Therefore, insulin actions on GABAergic efferent receptor causes an inhibition of pulsatile GNRH release, neurons, via modulation of the GABA postsynaptic

but the effect of GABAA receptor activation can be either response, may explain some of insulin’s central effects excitatory or inhibitory depending on the chloride on GNRH release.

Leptin Genetic background Table 1

Insulin DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Agrp nNOS Kiss1 Camk2a Gnrh Pomc Sf1 Nestin neo/neo +PMV-AAV-Flp LepR POMC Agrp db/db ob/ob ob/ob ob/ob ob/ob ob/ob ob/ob Vglut2 Vgat Gnrh Gnrh Kiss1 Pomc Agrp Vglut2 Vgat Review -cre + -cre + -cre + -cre + -cre + -cre + -cre + -Cre + -cre + -cre + -cre + -cre + -cre +

-cre + + + -cre + -cre + -cre + -cre + Nos1 Nos1 Gene deletionstudies:summaryofthemetaboliccontrolfertility. -cre + LepR LepR InsR LepR InsR LepR LepR InsR InsR InsR LepR LepR InsR LepR LepR InsR LepR InsR −/− −/− -flox LepR -flox -flox -flox -flox -flox -flox -flox -flox -flox -flox -flox -stop-flox -flox -flox -flox -stop-flox -flox -flox Genetic phenotype AgRP-specific Nitric oxide Kisspeptin- Forebrain neuron- GNRH-specific POMC-specific SF-1-specific LepR Brain-specific InsR PMV-restricted POMC-restricted Agrp-restricted LepR-deficient Leptin-deficient Leptin-deficient Leptin-deficient Leptin-deficient Leptin-deficient Leptin-deficient Glutamate- GABA-specific GNRH-specific GNRH-specific Kisspeptin- POMC-specific AgRP-specific Glutamate- GABA-specific LepR KO neurons specific LepRKO specific LepRKO LepR KO LepR KO KO KO LepR expression LepR expression LepR expression specific LepRKO LepR KO InsR KO InsR KO specific InsRKO InsR KO LepR KO specific InsRKO InsR KO m

evans and Printed inGreatBritain g

anderson Manipulation – – – – – – – – – – – – – – Leptin-treated – Agrp-deficient Agrp-ablated Leptin-treated – HFD feeding – – – – – – of reproduction Nutritional regulation Published byBioscientifica Ltd. phenotype Metabolic Overweight Obese Normal body Obese Normal body Overweight Overweight Overweight Obese Mildly overweight Obese Overweight Overweight Obese Restored body Improved body Obese Restored body Restored body Obese Obese Normal body Normal body Normal Normal body Normal body Mildly overweight weight weight weight control weight control weight control weight control weight weight weight weight phenotype Reproductive Normal Impaired estrus Normal Infertile Normal Normal Normal Normal Delayed puberty, Normal Rescued fertility – Rescued fertility Infertile Infertile Infertile Rescued fertility Rescued fertility Rescued fertility Infertile Protected from Normal Normal Normal Normal Normal Normal

fertility cyclicity, normal subfertile infertility HFD-induced Downloaded fromBioscientifica.com at09/24/202102:55:05PM 58 References van deWall Leshan Donato Quennell Quennell van deWall Bingham Zuure Zuure Bruning Donato Huo O Egan&GM Hummel Bellefontaine Bellefontaine Sheffer-Babila Wu Mounzih Ingalls DiVall Divall Evans Konner Konner Evans Evans (2009) (2009) (2010) (2008) (2008) lished observations) Anderson (unpub (2014) (2014) (2013) Zhang : 2 et al et al et al et al et al et al et al et al et al et al , et al

et al et al et al et al et al . (2012) et al Shi et al . (2009) (Continued) et al et al et al et al . (2010) . (2014 . (2014 . (2014 . (2013) . (2013) . (2015) . (1950)

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Table 1 Continued.

Metabolic Reproductive Genetic background Genetic phenotype Manipulation phenotype phenotype References Camk2a-cre + InsR-flox Forebrain – Mildly overweight Normal Evans et al. (2015) neuron-specific InsR KO Leptin + insulin Pomc-cre + InsR-flox + LepR-flox POMC-specific – Overweight Subfertile Hill et al. (2010) LepR and InsR KO Kiss1-cre + InsR-flox + LepR-flox Kisspeptin- – Normal body Altered pubertal Qiu et al. (2015) specific LepR weight timing and InsR KO Other Ghrelin−/− Ghrelin-deficient – Normal body Normal Sun et al. (2003) weight Ghsr−/− Ghrelin receptor- – Underweight – Sun et al. (2008) deficient Nestin-Cre + Sf1 flox/− Brain-specific SF1 – Normal body Impaired estrus Kim et al. (2010) KO weight cyclicity, subfertile

Glutamate-expressing neurons LH secretion occurs in a kisspeptin-independent manner (Garcia-Galiano et al. 2012). Furthermore, neurons in the Glutamate is the primary excitatory neurotransmitter ventral premamillary nucleus (PMV) of the hypothalamus, used by the majority of neurons in the CNS, and a body which mediate some of leptin’s metabolic influences of evidence demonstrates glutamate regulates GNRH on GNRH function (Donato et al. 2011), are almost neurons’ excitability and thus secretion. As reviewed exclusively glutamatergic (Kocsis et al. 2003), supporting by Iremonger and coworkers (Iremonger et al. 2010), a role for glutamate-expressing neurons in the metabolic many studies have shown that glutamate agonists and control of fertility. antagonists injected into the brain can stimulate or To investigate the direct effects of leptin and insulin inhibit LH secretion, respectively (Lopez et al. 1990, Brann signaling via glutamatergic neurons in the metabolic & Mahesh 1995, Ping et al. 1997). Glutamate likely exerts regulation of fertility, our lab generated glutamate-

Journal of Molecular Endocrinology its influence via direct effects on GNRH neurons, as Tena- specific LepR KO and InsR KO mice. In contrast to the Sempere’s lab demonstrated that glutamate-stimulated

Table 2 Neuropeptide and transmitter co-expression.

Primary neuropeptide/ transmitter population Sub-population Co-expression Estimated co-expression (%) References AgRP/NPY ARC GABA ≤100 Marshall et al. (2016) POMC/CART ARC GABA <40 Wittmann et al. (2013) ARC Glutamate <60 Wittmann et al. (2013) Kisspeptin AVPV Glutamate <25 Cheong et al. (2015) AVPV Dopamine ≤50 Skrapits et al. (2015) ARC GABA <25 Cheong et al. (2015) ARC Glutamate <75 Cheong et al. (2015) ARC GABA <15 Marshall et al. (2016) nNOS ARC GABA <50 Marshall et al. (2016) SF1 VMH Glutamate ≤75 Tong et al. (2007a,b) VMH GABA ≤20 Tong et al. (2007a,b) Dopamine ARC GABA ≤80 Marshall et al. (2016) VTA GABA ≤40 Merrill et al. (2015) VTA Glutamate ≤20 Kawano et al. (2006) AVPV Kisspeptin ≤50 Skrapits et al. (2015)

AgRP, agouti-related peptide; ARC, arcuate nucleus; AVPV, antero-ventral peri-ventricular nucleus; CART, cocaine-amphetamine-related-transcript; nNOS, neuronal nitric oxide synthase; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; SF1, steroidogenic factor 1; VMH, ventro-medial hypothalamus; VTA, ventral tegmental area.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0212 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:55:05PM via free access Journal of Molecular Endocrinology the fasting-inducedsuppression ofLHreleasethatwas under normalconditions, they wereprotectedagainst knockout micedidnotexhibit afertilityphenotype ( expression andconcomitant suppressionofGNRHdrive ( reproductive function. are thus aptly equipped to integrate metabolic and GNRH release( thereby promotingNPY/AgRP-inducedsuppression of leptin andinsulin,ghrelinstimulatesNPY/AgRPneurons, ( melanocortin receptor (MC4) signaling stimulatory mediated, atleastinpart,viaAgRP’s antagonismof effectsofAgRPonGNRHneuronsarelikely inhibitory AgRP onGNRHneurons.Itshouldbenotedthatthe 2007 AgRP-expressing neurons( ( byghrelin-expressingneurons and arealsoinnervated insulin ( NPY/AgRP neurons,inturn,aredirectlymodulatedby Cone 2005 effectsonGNRHneurons( inhibitory orexigenic neuropeptidesshowntohavepredominantly (NPY) andagouti-relatedpeptide(AgRP),whichareboth (ARC) ofthehypothalamusco-expressneuropeptideY A subsetofGABAergicneurons in thearcuate nucleus NPY/AgRP-expressing neurons critically involved. but unlikeleptinsignalinginGABAneurons,itisnot to permit puberty onset and reproductive function, leptin signaling in glutamate neurons may be sufficient at theonsetofpuberty. Althoughspeculative,itappears suggest thePMVisakeysiteforleptin’s permissiveaction PMV is almost exclusively glutamatergic, and these data fertility ( LepR showedrescuedpubertyonsetandimproved exhibiting PMV-restricted re-expressionofendogenous Forexample,LepR-nullmice evidence suggestsotherwise. mediator ofthemetaboliccontrolfertility, some Although thesestudiessuggestglutamateisnotacritical exhibited normalHPGaxisfunction( ( LepR KOmiceexhibited normal pubertyonsetandfertility puberty andreducedfecundity, theglutamate-specific GABA-specific LepRKOmice,whichexhibiteddelayed Ollmann Cowley Zuure Kalamatianos Korner DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Review Physiologically, fastingcausesanincrease in ), thereby reducing the inhibitory toneofNPY/ ), therebyreducingtheinhibitory et al t al et Konner Donato t al et et al , . 2013 Vulliemoz . 2001 . 2003 t al et . 1997 Lebrethon et al et al ). Glutamate-specificInsRKOmicealso ) and . 2008 . 2011 . 2007 ). InsulinandleptininhibitNPY/ , et al Cowley et al Npy ). Interestingly, although NPY- ). Asmentionedpreviously, the Sato . 2005 ) andleptin( ( et al . 2007 et al Brady m ,

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and peptide,despitebeingenergyreplete,insulin show increasedhypothalamicexpressionof activation. Accordingly, insulin-deficientdiabeticrats ghrelin receptorpromotestonicNPY/AgRPneuronal Schwartz 2004 in responseto a fast ( observed may furtherpromotetheincreasedNPYexpression an increaseincirculating ghrelinconcentration,which 1997 fasted animals( in wild-type control mice ( observed ‘rescue’ mice,theNPY/AgRP-LepR ‘rescue’miceexhibited onset ( exclusively inthePMVwasalso sufficienttoinducepuberty sufficient topermitfertility ( that leptin signalingexclusivelyin NPY/AgRP neurons is neurons exert on reproductive function and also reveal tone NPY/AgRP-expressing both the powerful inhibitory involved inthesuppressionofGNRH.Thesedatahighlight respectively), it appears that they are both independently response tonutritionalstress(fastingandLepRdeficiency, shown toexhibitimprovedreproductivephenotypes in both NPY-knockout miceandAgRP-deficientwere AgRP-induced inhibitionofreproductivefunction.As NPY/AgRP signalingalonecansufficientlyblockNPY/ demonstratingthatleptin- unpublished observations), in NPY/AgRPneurons(OEgan&GMAnderson, deficient mice by restoring leptin sensitivity exclusively LepR- fertility canbecompletelyreinstatedinotherwise alone (vsneuronalablation)inLepR-null( tolerance ( restore their fertility, food intake regulation and glucose in leptin-deficient( was shownthatablatingNPY/AgRP-expressingneurons must restrainNPY/AgRPneuronstopermitfertility, it NPY/AgRP activity. suggests insulin is critically involved in restraining tonic administration restoredNPYlevels( have constitutiveactivity( However, asmentionedpreviously, ghrelinreceptors or leptindecreased thought tomediatethiseffect,astreatmentwithinsulin inresponsetofastingare insulin concentrationsobserved to lowenergyavailability. Thedecreasedleptinand whereby HPGfunctionbecomessuppressedinresponse suggesting NPYplaysacriticalroleinthemechanism Babila was alsoabletorescuetheirHPGaxisfunction( of reproduction Nutritional regulation Published byBioscientifica Ltd. As mentionedpreviously, reactivationofLepR Further supportingtheideathatinsulinand/orleptin , t al et Korner Donato Wu . 2013 et al et al et al ), so even in the absence of fasting,the Schwartz ). Lastly, ourlabrecentlyshowedthat . 2001 . 2011 . 2012 Npy

ob/ob mRNAandpeptideexpressionin ). Fasting is also accompanied by Downloaded fromBioscientifica.com at09/24/202102:55:05PM ). However, unlikethePMV-LepR et al ). Additionally, AgRPdeficiency ) diabeticmicewasableto Vulliemoz Holst . 1991 Asakawa t al et Abe Hill & Levine 2003 , 58 Wang &Leibowitz et al et al . 2003 : 2 t al et . 2005 . 1991 db/db Npy , Holst & . 2001 ). Sheffer- mRNA R114 ) mice ). This via freeaccess ). ). ), Review m c evans and g m anderson Nutritional regulation 58:2 R115 of reproduction

a slightly attenuated body weight phenotype. Although it POMC neurons, such that in the absence of leptin-POMC thus remains a possibility that the improved reproductive signaling, sufficient compensation occurs via insulin, and function observed in the NPY/AgRP-LepR ‘rescue’ mice vice versa. However, despite exhibiting subfertility, the might be due in part to their improved body weight, this mice lacking both leptin- and insulin-POMC signaling seems unlikely as, in addition to the PMV-LepR ‘rescue’ were still able to reproduce, suggesting insulin and leptin experiment, there are several accounts demonstrating can act via other circuitry to permit sufficient activation that fertility can be maintained in morbidly obese mice of the HPG axis, further highlighting how redundancy in (Bates et al. 2003, Singireddy et al. 2013). the mechanisms whereby nutritional signals reach GNRH neurons confers reproductive resilience.

POMC/CART-expressing neurons Kisspeptin-expressing neurons Acting in opposition to the NPY/AgRP neurons are ARC neurons encoding pro-opiomelanocortin (POMC, a The endogenous G-protein-coupled receptor 54 (GPR54) precursor of the anorexigenic melanocortin peptides) ligand, kisspeptin, has been identified as the most potent and cocaine–amphetamine-related transcript (CART) secretagogue of GNRH (Irwig et al. 2004) and is likewise (POMC/CART neurons). These neurons play a key role in implicated in the timing of puberty onset (Han et al. energy homeostasis by promoting satiety and suppressing 2005) and the mechanism whereby energy status is feeding (Baskin et al. 1999, Meister 2007); yet, they have relayed to the reproductive axis (Tena-Sempere 2006, also been shown to promote GNRH neuron activity, Castellano et al. 2010, De Bond et al. 2016). Although presumably via direct actions (Leranth et al. 1988, Roa kisspeptin gene (Kiss1) expression is primarily regulated & Herbison 2012, True et al. 2013). Sub-populations of by gonadal steroid hormones (Smith 2009), it is also POMC neurons have been shown to co-express GABA modulated by metabolic status such that its expression and glutamate (Table 2). Perhaps not surprisingly, POMC/ becomes reduced in response to metabolic stress, such CART neurons are regulated by insulin, leptin and ghrelin as fasting (Castellano et al. 2005) or prolonged high-fat (Havel et al. 2000, Cowley et al. 2001, 2003, Balthasar et al. diet feeding (Quennell et al. 2011). Approximately 40% of 2004, Williams et al. 2010). Peripheral ghrelin peptide ARC kisspeptin neurons were shown to express the gene indirectly inhibits the activity of POMC/CART neurons for LepR (Smith et al. 2006) in one report, but subsequent in mice (Cowley et al. 2003), but POMC/CART neurons work suggests a more modest level of co-expression may also be directly modulated by ghrelin-expressing (Louis et al. 2011, Cravo et al. 2013) and failed to show

Journal of Molecular Endocrinology neurons via synaptic communication (Guan et al. 2008). direct leptin–kisspeptin signaling (Quennell et al. 2011). Leptin activates POMC neurons to promote satiety, and InsR protein expression was also observed in a subset of in the absence of leptin-POMC signaling, an obesity kisspeptin immunoreactive neurons (Evans et al. 2014a). phenotype results (Balthasar et al. 2004). Insulin’s Physiologically, kisspeptin treatment to women with appetite-suppressing effects are also largely mediated via acquired GNRH deficiency due to low energy availability POMC neurons (Benoit et al. 2002); yet, in the absence of was able to stimulate GNRH/LH release (Jayasena et al. direct insulin-POMC signaling, mice exhibit normal body 2009, 2010), suggesting that neuroendocrine integration weight regulation (Konner et al. 2007), presumably due of nutritional signals converge upstream of, or directly to the developmental compensation provided by leptin. on, kisspeptin neurons. Accordingly, leptin treatment to These data suggest leptin actions on POMC neurons are ob/ob mice increased Kiss1 mRNA expression (Smith et al. required for normal energy homeostasis, whereas insulin 2006), whereas ghrelin administration was shown to actions are not. reduce kisspeptin expression and LH pulse frequency With regard to fertility, insulin or leptin actions alone in ad libitum fed rats (Forbes et al. 2009). Also, insulin- on POMC neurons do not appear to play a critical role in dependent diabetic rats exhibit reduced kisspeptin mRNA conveying energy status to the HPG axis, as mice exhibiting levels (Castellano et al. 2006). Interestingly, insulin POMC-specific deletion of either LepR Balthasar ( et al. administration did not rescue the reduced kisspeptin 2004) or InsR (Konner et al. 2007) exhibited completely gene expression observed in these diabetic rats; yet, leptin normal fertility. Interestingly, mice exhibiting POMC- administration was sufficient to restoreKiss1 mRNA levels specific deletion of both LepR and InsR did present with and LH concentration (Castellano et al. 2006). reduced fertility, but not infertility (Hill et al. 2010). This Although ample evidence suggests leptin and insulin suggests leptin and insulin exert overlapping control of modulate kisspeptin neurons, their direct influences are

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0212 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:55:05PM via free access Journal of Molecular Endocrinology sufficient torescuetheonset ofpubertyinfood-restricted ( which occursinakisspeptin-independent manner to stimulateLHreleasein mice ( status totheHPGaxis. equipped totransduceinformationregardingnutritional by insulin( Cunningham regulated by leptin ( neurons. In turn, GALP neurons express LepR and are 2006 with enhancedgreenfluorescentprotein( in transgenicratswhichGNRHneuronsweretagged and axo-dendriticsynapticcontactswithGNRHneurons terminalswerealsofoundtomakeaxo-somatic nerve the rathypothalamus( fibers makeapparent contacts withGNRH neurons in cell bodies are primarily located in the ARC, but their Crown to themetaboliccontroloffertility( represent anotherpopulationofneuronsthatcontributes Galanin-like peptide(GALP)-expressingneurons GALP-expressing neurons cause reproductiveimpairments( to adulthoodenergyhomeostasis( of themelanocortinsystemandthuscausedisturbances which areknowntoimpairhypothalamicdevelopment explain, atleastinpart,whyprenatalnutritionalinsults, Pomc ARC kisspeptinneuronswererecentlyshowntoarisefrom downstream ofPOMCneurons.Interestingly, overhalfof conveyed toGNRHneuronscouldbebothupstreamand role inthemechanismwherebynutritionalstatusis activity ( POMC neuronsandindirectlyinhibitNPYneuronal 2016 indirectly viaPOMCneurons( likely thatleptin’s effectsonkisspeptinaremediated kisspeptin–GNRH signalingpathway, anditisthus recently documentedanovelleptin–melanocortin– ( fertile, yet,haddelayedpubertaltiming completely specific deletionofbothInsRandLepRwerealso normal HPG axis function. Mice exhibiting kisspeptin- ( exhibiting kisspeptin-specific deletion ofeither InsR not requiredfornormalreproductivecontrol,asmice Garcia-Galiano Qiu Evans DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Review Physiologically, GALP administration was shown et al ), suggestingGALPcandirectlyregulateGNRH ). Conversely, kisspeptinwasshowntodirectlyexcite -expressing progenitors( et al t al et . 2015 Fu &vandenPol2010 . 2007 . 2014 Fraley et al ). However, Manfredi-Lozanoandcoworkers t al et , . 2002 a t al et Shioda ) orLepR( Jureus . 2012 Takatsu . 2004 ) andarealsodirectlymodulated et al et al ), andGALPinfusionwas . 2011 Sanz et al ). GALPneuronsarethus Donato . 2000 ), soitappears kisspeptin’s m Dupont Manfredi-Lozano

evans , Cunningham 2004 Takatsu t al et . 2015 and et al ). GALP-positive et al Printed inGreatBritain Takenoya . 2011 t al et g . 2012 . 2013 ). Thismay

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anderson . 2005 ) retain . 2001 t al et ), can ). et al ), . , . , SF1 peptidedeletion.Inamore refinedexperiment,itwas phenotypewasadirectresultof whether theobserved and neuronalorganization, soitremainsunknown mice also exhibited impaired hypothalamic development obesity ( expression leads to impaired fertility and late-onset 2010 ( key roleinglucosehomeostasisandappetitecontrol hypothalamus (VMH),whichisknowntoplay a restricted to,andlargelycomprises,theventro-medial factor 1 (SF1) ( co-express neuropeptides ( Like GABAergicneurons,manyglutamatergicneurons SF1-expressing neurons coordinate theireffectsonfeedingbehaviorandfertility. neurons mayexhibitbi-directionalcommunicationto actions ( were neurons inthedorsomedialnucleusofhypothalamus their activity( on fertility, asGALPwasnotabletodirectlymodulate AgRP neuronsareinvolvedinmediatingGALP’s effects However, itdoesnotappearARCPOMC/CARTorNPY/ was abletodirectlystimulateGNRHneuronsisolated ( and insulin to rescue reproductive function in these rats demonstrating thatGALPmediatestheabilityofleptin was preventedwhenaGALPantibodyadministered, function in insulin-dependent diabetic rats; yet, this effect and leptinco-administrationrescuedreproductive of GALPexpression.Furthermore,subcutaneousinsulin suggesting insulinandleptinexhibitoverlappingcontrol Galp 48-h fast,andinsulinorleptinadministrationincreased Galp exhibiting insulin-dependentdiabeteshavereduced and alsofacilitatesfertility demonstrating GALPismodulatedbynutritionalsignals weanling maleandfemalerats( Kiss1 via kisspeptinneurons,asGALPadministrationincreased neurons. However, GALP’s effectsmayalsobemediated previously, GNRH GALPneuronsdirectlyinnervate from therat( administration reversedthiseffect( mRNA comparedtocontrolanimals,andbraininsulin of reproduction Nutritional regulation Tong Stoyanovitch Published byBioscientifica Ltd. GALP’s effectsonHPGfunctionmaybedirect,asGALP showntomediateGALP’s acuteorexigenicfeeding mRNAlevels( mRNAlevelswerealsoreducedinratsexposedtoa ). Interestingly, brain-specific deletion of SF1 peptide mRNAinfood-restrictedrats( t al et Kuramochi Kim . 2007 et al Kuramochi t al et Kuramochi Tong b . 2005 . 2010 ), aswellreproduction( et al Jureus

t al et . 2006 Downloaded fromBioscientifica.com at09/24/202102:55:05PM ). et al ). However, theseSF1-deficient Table 2 et al t al et . 2007 ), suggestingGALPandNPY . 2005 in vivo . 2000 . 2005 ), such as steroidogenic a ). SF1 expression is ) and,asmentioned Mohr , Fraley . Accordingly, rats ). Incontrast,NPY 58 Mohr Fraley : 2 t al et t al et t al et et al Kim . 2012 . 2004 . 2012 . 2004 R116 t al et Galp via freeaccess ). ), ). ), .

Review m c evans and g m anderson Nutritional regulation 58:2 R117 of reproduction

demonstrated that SF1 neuron-specific deletion of LepR neurotransmitters contribute to the regulation of hedonic leads to obesity without causing reproductive impairments eating. Nevertheless, these studies identify a role for both (Bingham et al. 2008). The former finding, albeit with its the ARC and VTA TH-expressing neurons in the regulation considerable caveats, may suggest SF1 peptide is critically of feeding behavior. involved in the regulation of fertility; yet, the latter With regard to fertility, dopamine has been shown to result suggests that leptin signaling via SF1-expressing exert both acute and tonic inhibition of GNRH neuron neurons is not, despite its critical role in regulating energy activity (Liu & Herbison 2013). Using electrophysiology homeostasis. Leptin’s roles in the control of metabolism in mouse brain slices, Liu and Herbison demonstrated and reproduction therefore appear dissociated, further that bath application of dopamine potently inhibited the highlighting the complexity of the neuroendocrine firing rate of ~50% of GNRH neurons, whereas application integration of metabolic and reproductive function. of dopamine receptor antagonists increased the basal firing of ~1/3 of GNRH neurons. Approximately 20% of GNRH neurons were shown to receive dopaminergic innervation Tyrosine hydroxylase-expressing neurons from the anteroventral periventricular nucleus (Liu & Tyrosine hydroxylase (TH)-expressing neurons, Herbison 2013); however, identifying whether the ARC which synthesize and release catecholamines (either or VTA dopamine population(s) are involved in the noradrenaline or dopamine), are also modulated by leptin, regulation of GNRH remains unclear. insulin and ghrelin (Hommel et al. 2006, Konner et al. In order to characterize the functional role of insulin 2011, Zhang & van den Pol 2016) and are involved and leptin signaling via dopamine neurons, mice exhibiting in the regulation of energy homeostasis (Khanh et al. TH-specific deletion of InsR or dopamine-specific deletion 2014) and fertility (Clarkson & Herbison 2011). Several of LepR were generated. Interestingly, although the distinct TH-expressing neuronal populations have been TH-specific InsR KO mice exhibited an increased body identified and anatomically characterized; yet, the major weight phenotype (Konner et al. 2011), the dopamine- populations thought to be involved in the regulation of specific LepR KO mice showed completely normal feeding energy homeostasis are the ARC and ventral tegmental behavior and body weight, even when challenged with area (VTA) dopaminergic populations. The TH neurons a high-fat diet (Liu et al. 2011). Unfortunately, their in the ARC, referred to as tuberoinfundibular dopamine reproductive phenotypes were not assessed. (TIDA) neurons, were recently shown to play an orexigenic role in homeostatic feeding behavior (Zhang & van den NOS-expressing neurons Journal of Molecular Endocrinology Pol 2016). Accordingly, ghrelin was shown to evoke direct excitatory effects in these neurons. A subset of these Nitric oxide synthase (NOS) neurons, which produce neurons were also shown to co-express GABA, which nitric oxide, comprise a subset of hypothalamic neurons was involved in mediating some of the orexigenic effects recently shown to mediate leptin’s effects on the HPG (Zhang & van den Pol 2016). The TH-expressing neurons axis. As mentioned previously, leptin treatment restores in the VTA of the midbrain are thought to be involved HPG axis function in leptin-deficient mice; yet, in the in the regulation of hedonic (vs homeostatic) feeding absence of nitric oxide signaling, leptin was unable behavior (Volkow et al. 2011). Accordingly, intra-VTA to induce puberty in ob/ob mice (Bellefontaine et al. leptin infusion was shown to decrease dopamine neuron 2014). This suggests nitric oxide signaling facilitates firing and reduce feeding Trinko( et al. 2011), whereas leptin’s permissive effects on puberty onset and ghrelin infusion into the VTA stimulated dopamine release fertility. Furthermore, neuronal NOS-knockout mice are and dramatically increased food intake (Abizaid 2009). hypogonadic and infertile (Gyurko et al. 2002), and mice Although insulin does not appear to directly modulate exhibiting NOS neuron-specific deletion of LepR exhibit dopamine release, it was shown to increase dopamine delayed puberty and hyperphagic obesity (Leshan et al. reuptake and thus, like leptin, caused an overall reduction 2012). However, even though NOS expression identified in dopamine signaling, leading to suppressed food intake the population of neurons involved in mediating leptin’s (Mebel et al. 2012). Although dopamine appears to be the effects on metabolic and reproductive function, the major effector of these observations, sub-populations of authors suggest it is unlikely that nitric oxide signaling VTA dopamine neurons have been shown to co-express itself was responsible for leptin’s observed metabolic GABA (Olson & Nestler 2007) and glutamate (Alsio et al. effects because NOS-deficient mice show no obvious 2011), and it thus remains a possibility that these metabolic phenotype (Huang 2000). Sub-populations of

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0212 Printed in Great Britain Downloaded from Bioscientifica.com at 09/24/2021 02:55:05PM via free access Journal of Molecular Endocrinology disruption of neural signal transducer and activator regard tothemetaboliccontrol offertility. Forexample, for discretesignalingpathways havebeenestablishedwith 2011 Carvalheira Schwartz 2003 demonstrated ( to theirrespective receptors being activated has been between theintracellularpathwaysactivatedinresponse for example,yetahighdegreeofoverlapandinteraction exert theirinfluenceonspecificneuronalpopulations, Leptin andinsulinmightactviauniquereceptors to intracellular signalingmoleculesshouldnotbeignored. of metabolic and reproductive function, the role of hormone–neuron interactionsinvolvedintheintegration emphasis isoftenplacedonidentifyingthespecific Intracellular signalingmolecules Other considerations ultimately regulateGNRHdrive. inputs from the GNRH neuronal network that stimulatory and still contributetothenetimpactofallinhibitory ignored as under normal physiological conditions, they of these‘lesserinvolved’populationsshouldnotbe involved ( of reproductivefunctionappearstobemorecritically 2015 2007 energy availabilitysuppressesGNRHdrive( are alsoimplicatedinthemechanismwherebylow signaling ( regulation ofRFRPneuronsappearstooccurviaindirect LepR ( hormone neurons,wererecentlyshowntoco-express mammalian orthologstoaviangonadotropin-inhibiting small subpopulationofRFRPneurons,whicharethe hormone (MCH)andorexin-expressingneurons.A RFamide-related peptide(RFRP),melanin-concentrating involvement ofothers.Amongthese,forexample,are control offertility, there isalsoevidence supporting the arguably thekeypopulationsinvolvedinmetabolic Although theaforementionedneuronalpopulationsare Other neuronal populations downstream metaboliceffects. one oftheseneurotransmittersisresponsibleforleptin’s glutamate ( NOS neurons co-express GABA ( DOI: 10.1530/JME-16-0212 http://jme.endocrinology-journals.org Review , ), yet,theinfluenceofNPY/AgRPinsuppression , Burgos-Ramos Backholer Poling Rizwan Wu Lin et al et al , et al Niswender t al et Mirshamsi et al . 2005 et al . 2014 . 2004 . 2012 et al . 2009 , . 2014 Morris &Rui2009 . 2011 ), forexample.However, leptin’s ), anditisthereforepossiblethat et al et al ). Nevertheless,theinfluence , Wu ). MCH and orexin neurons ). Furthermore,criticalroles . 2004 . 2001 et al Marshall m

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anderson . 2005 t al et et al et al ) and . , . . reproductive function remained intact ( STAT3 inactivationwasrestrictedtoLepR-expressingcells, inactivation ofleptin-inducedsignaling.However, when in theseSTAT3-knockout micemightbeduetothe activation, onemightassumethephenotypeobserved infertility inmice( of transcription3(STAT3) causesobesity, diabetesand mTOR signaling,phosphatidylinositol-3-kinase(PI3K) Roa &Tena-Sempere 2014 puberty infood-restrictedfemalerats( puberty andalsobluntedtheabilityofleptintopromote that mTORinactivationinhibitedthegonadotropicaxisat reproductive function.Roaandcoworkersdemonstrated has beenidentifiedasacentralregulatorofmetabolicand to amultitudeoffactors,includinginsulinandleptin, of rapamycin(mTOR), which canbeactivatedinresponse reproductive function.Similarly, themammaliantarget leptin-induced STAT3 activation may be required for 2013 release ( the effectsoffastingtosuppressGNRH-stimulatedLH Moenter (2011) availability playsarole.Asreviewedby yet, thereisalsoampleevidencesuggestingglucose play an important role in the metabolic control of fertility; intracellular signalingcascadestheyinitiateundoubtedly Cellular energysensing nutritional signalsonfertility. molecules playintheneuroendocrineintegrationof understanding oftherolesthatintracellularsignaling others, demonstratetheimportanceofamorecomplete by reproductive functionbecomessuppressed,asreviewed are thought to play a role in the mechanism whereby chronic under-andover-nutrition,theseimpairments in response to insulin-induced PI3K signaling are observed and reproductivefunction.Impairmentsinleptin-and/or signaling isalsoconsideredakeyintegratorofmetabolic hypothalamic glucosesensing, whichinturncould there isevidencesuggesting nutritionalsignalsmodulate induced LHsecretion( override thefasting-induced suppressionofGNRH- energy balance(i.e.fasted or fed),yet,wasunableto led toanincreaseinLHconcentrationregardless of For example,blockadeofK perturbations viatheseK K experiments showGNRHneuronsexpressATP-sensitive of reproduction Nutritional regulation + Published byBioscientifica Ltd. (K Acosta-Martinez (2011) ), highlighting that STAT3 signaling other than ATP Bucholtz ) channelsandaresensitivetometabolic , adecreaseinglucoseavailabilitymediates t al et Gao

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Review m c evans and g m anderson Nutritional regulation 58:2 R119 of reproduction

influence GNRH neuronal function (Bruning et al. neuron adhesiveness in the mouse hypothalamus 2000, Diggs-Andrews et al. 2010). Insulin and leptin, (Sandau et al. 2011b), and it was shown that astrocyte-to-

for example, have been shown to activate KATP channels GNRH neuron adhesiveness via SynCAM1 is important in (Spanswick et al. 2000, Mirshamsi et al. 2004). the control of female sexual development. For example, Adenosine monophosphate (AMP)-activated protein female mice expressing a SynCAM1 dominant negative kinase (AMPK), long considered a cell-autonomous form specifically in astrocytes exhibited delayed onset of energy sensor, can also act as an integrative metabolic puberty, disrupted estrus cyclicity and reduced fecundity sensor in the brain (Ramamurthy & Ronnett 2006) and (Sandau et al. 2011a). Astroglial cells, therefore, play a may therefore modulate GNRH neuronal activity, either role in GNRH neuronal function and may facilitate the directly or indirectly by stimulating or inhibiting neurons nutritional regulation of fertility. in the GNRH neuronal network. The activity of AMPK Tanycytes, which are specialized bipolar glial cells is normally regulated by immediate glucose availability, located in the ARC and median eminence, also play a but is also increased in the presence of orexigenic role in GNRH release via extension and retraction of their stimuli (e.g. AgRP and ghrelin) and decreased in the end-foot processes between GNRH synaptic terminals presence of anorexigenic stimuli (e.g. insulin and leptin) (Rodriguez et al. 2005, Baroncini et al. 2007). As reviewed (Minokoshi et al. 2004). This permits the possibility that by Levin and coworkers, tanycytes express tight junctions whole body energy status (i.e. fuel reserves) acts in concert that regulate the permeability of the brain parenchyma with immediate glucose availability to modulate the to CSF and may therefore have the capacity to integrate activity of neurons. Minokoshi and coworkers propose a number of signals associated with energy status a model for how orexigenic and anorexigenic signals, (Levin et al. 2004). Tanycytes express glucose transporters,

through AMPK activation and suppression, respectively, as well as KATP channels (Garcia et al. 2003), which supports result in an integrated metabolic response required the possibility that they act as glucose sensors and as a for the regulation of food intake and energy balance possible conduit whereby peripheral nutritional signals (Minokoshi et al. 2004), and this could presumably be the could modulate GNRH neuronal activity. Accordingly, case for reproductive function as well. tanycytes were shown to respond rapidly to changes in glucose and ATP concentration (Frayling et al. 2011). Astroglial cells It is also possible that astroglial cells are involved in the mechanism whereby nutritional signals Stress responses as metabolic modulators of HPG modulate GNRH neuronal activity (Baroncini et al. 2007, axis function Although the evidence supporting the Journal of Molecular Endocrinology Ojeda et al. 2008). Firstly, astrocytes play an important linkage between metabolic impairments and reproductive role in glucose metabolism (Yi et al. 2011), which, as disturbances is strong, others have proposed the idea of a discussed previously, is an important regulator of GNRH stress-related mechanism in which reproductive function neuronal function. Secondly, leptin and insulin signaling is compromised secondary to the activation of the stress- via astrocytes has been demonstrated (Yi et al. 2011). response systems: the hypothalamic–pituitary–adrenal Astrocytic insulin signaling modulates glucose metabolism (HPA) and sympathoadrenal axes (Tilbrook et al. 2000, in primary human astrocytes (Heni et al. 2011) as well 2002). Although this review has focused on metabolic as in vivo (Garcia-Caceres et al. 2016), which suggests stress, it has also been shown that immune stress (i.e. insulin actions on astrocytes could indirectly mediate inflammation), psychosocial stress, environmental stress the effects of glucose availability on GNRH neuronal and physical stress are associated with alterations in GNRH function. Leptin signaling in astrocytes was also recently secretion and subsequent reproductive disturbances shown to play an active role in the hypothalamic control (O’Byrne et al. 1988, Chen et al. 1992, Li et al. 2004a,b, of feeding (Kim et al. 2014). Recently, astrocytes were Berga 2006, 2008, Kinsey-Jones et al. 2009, Knox et al. shown to control food intake by inhibiting AgRP neuron 2009). It therefore stands to reason that stress itself activity (Yang et al. 2015), which suggests astrocytes exerts an inhibitory effect on reproductive function. are indirectly able to promote fertility as restraining However, some evidence suggests the influence of stress AgRP neurons would presumably facilitate GNRH drive, cannot be easily separated from its impact on nutritional as mentioned previously. Furthermore, Sandau and signals, suggesting the final common pathway leading to coworkers demonstrated that the synaptic cell adhesion compromised reproductive function may be perceived low molecule, SynCAM1, mediates astrocyte-to-GNRH energy availability (Loucks & Redman 2004, Berga 2008).

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