The Role of RFRP Neurons in the Allostatic Control of Reproductive Function.

Reproductive function is critical for species survival; however, it is energetically costly and physically demanding. Reproductive suppression is therefore a physiologically appropriate adaptation to certain ecological, environmental, and/or temporal conditions. This 'allostatic' suppression of fertility enables individuals to accommodate unfavorable reproductive circumstances and safeguard survival. The mechanisms underpinning this reproductive suppression are complex, yet culminate with the reduced secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn suppresses gonadotropin release from the pituitary, thereby impairing gonadal function. The focus of this review will be on the role of RFamide-related peptide (RFRP) neurons in different examples of allostatic reproductive suppression. RFRP neurons release the RFRP-3 peptide, which negatively regulates GnRH neurons and thus appears to act as a 'brake' on the neuroendocrine reproductive axis. In a multitude of predictable (e.g., pre-puberty, reproductive senescence, and seasonal or lactational reproductive quiescence) and unpredictable (e.g., metabolic, immune and/or psychosocial stress) situations in which GnRH secretion is suppressed, the RFRP neurons have been suggested to act as modulators. This review examines evidence for and against these roles.

Dentistry responding in domestic violence and abuse (DRiDVA) feasibility study: a qualitative evaluation of the implementation experiences of dental professionals.

BACKGROUND: Domestic Violence and Abuse (DVA) is a persistent public health problem in the UK. Healthcare settings offer an opportunity to ask patients about DVA, either opportunistically or in response to the presence of injuries. However, it has been suggested that dental practices and dental teams have not been actively involved supporting adult patients when presenting with injuries that might have resulted from DVA. This qualitative study was conducted to satisfy the evaluative component of the Dentistry Responding in Domestic Violence and Abuse (DRiDVA) feasibility study. METHODS: In total, 30 participants took part in the study; nine associate dentists and practice principals/owners took part in one-to-one interviews and 21 auxiliary staff took part across two focus group discussion sessions. Data were analysed using the seven step Framework Analysis process. RESULT: Three key themes were identified from the data, focusing on barriers to enquiring about domestic violence and abuse, Facilitators of identification and referral of DVA in dental settings, and recommendations for further adaptation of intervention to dental settings. CONCLUSION: DVA training coupled with robust referral pathways to a named specialist DVA advocate increases knowledge and awareness of the signs of DVA and confidence in making onward referrals. Further research is needed to understand how to increase dental professional willingness to ask patients about DVA.

RFamide-Related Peptide Neurons Modulate Reproductive Function and Stress Responses.

RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes.

Barriers to help-seeking from healthcare professionals amongst women who experience domestic violence - a qualitative study in Sri Lanka.

BACKGROUND: Domestic violence (DV) is a major global public health problem which is associated with significant adverse consequences. Although Sri Lankan women who experience DV receive treatment from healthcare professionals (HCPs) for DV related physical and psychological problems, disclosure of DV within health services is quite low. This study explored barriers to disclosure of DV to HCPs among Sri Lankan women who experience DV. METHOD: This qualitative study took place in the Central Province of Sri Lanka. Twenty women who had experienced DV were recruited from Gender Based Violence Centers (Mithuru Piyasa Centers) and a toxicology unit of the two selected hospitals. Participants were purposefully selected using maximum variation sampling technique. In-depth interviews were conducted until data saturation was reached. Interviews were recorded, and analyzed using thematic analysis. RESULTS: Survivor related barriers to help seeking included women's lack of knowledge and perceptions about the role of HCPs, lack of confidence in HCPs, fear of repercussions, personal attitudes towards DV, and their love and loyalty towards the perpetrator. Women preferred it if HCPs initiated discussions about DV, and they valued it when HCPs could be confidential and protect their privacy, and give enough time for DV related issues during consultations. A perpetrator related barrier was the controlling behavior of the perpetrator. Social stigma and social and cultural norms about the role of women emerged as the socio-cultural constraints to disclosure. CONCLUSIONS: Barriers to help seeking for DV from HCPs exist at individual, healthcare level, and societal level. Community programs are needed to increase women's access to healthcare services and interventions should be implemented to develop effective, preventive, and supportive strategies at the healthcare system level.

Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.

Barriers to women's disclosure of domestic violence in health services in Palestine: qualitative interview-based study.

BACKGROUND: Domestic violence (DV) damages health and requires a global public health response and engagement of clinical services. Recent surveys show that 27% of married Palestinian women experienced some form of violence from their husbands over a 12 months' period, but only 5% had sought formal help, and rarely from health services. Across the globe, barriers to disclosure of DV have been recorded, including self-blame, fear of the consequences and lack of knowledge of services. This is the first qualitative study to address barriers to disclosure within health services for Palestinian women. METHODS: In-depth interviews were carried out with 20 women who had experienced DV. They were recruited from a non-governmental organisation offering social and legal support. Interviews were recorded, transcribed and translated into English and the data were analysed thematically. RESULTS: Women encountered barriers at individual, health care service and societal levels. Lack of knowledge of available services, concern about the health care primary focus on physical issues, lack of privacy in health consultations, lack of trust in confidentiality, fear of being labelled 'mentally ill' and losing access to their children were all highlighted. Women wished for health professionals to take the initiative in enquiring about DV. Wider issues concerned women's social and economic dependency on their husbands which led to fears about transgressing social and cultural norms by speaking out. Women feared being blamed and ostracised by family members and others, or experiencing an escalation of violence. CONCLUSIONS: Palestinian women's agency to be proactive in help-seeking for DV is clearly limited. Our findings can inform training of health professionals in Palestine to address these barriers, to increase awareness of the link between DV and many common presentations such as depression, to ask sensitively about DV in private, reassure women about confidentiality, and increase awareness among women of the role that health services can play in DV.

Leptin and insulin do not exert redundant control of metabolic or emotive function via dopamine neurons.

Leptin and insulin's hunger-suppressing and activity-promoting actions on hypothalamic neurons are well characterized, yet the mechanisms by which they modulate the midbrain dopamine system to influence energy balance remain less clear. A subset of midbrain dopamine neurons express receptors for leptin (Lepr) and insulin (Insr). Leptin-dopamine signaling reduces running reward and homecage activity. However, dopamine-specific deletion of Lepr does not affect body weight or food intake in mice. We hypothesized insulin-dopamine signaling might compensate for disrupted leptin-dopamine signaling. To investigate the degree to which insulin and leptin exert overlapping (i.e. redundant) versus discrete control over dopamine neurons, we generated transgenic male and female mice exhibiting dopamine-specific deletion of either Lepr (Lepr KO), Insr (Insr KO) or both Lepr and Insr (Dbl KO) and assessed their feeding behavior, voluntary activity, and energy expenditure compared to control mice. No differences in body weight, daily food intake, energy expenditure or hyperphagic feeding of palatable chow were observed between Lepr, Insr or Dbl KO mice and control mice. However, consistent with previous findings, Lepr KO (but not Insr or Dbl KO) male mice exhibited significantly increased running wheel activity compared to controls. These data demonstrate that insulin and leptin do not exert redundant control of dopamine neuron-mediated modulation of energy balance. Furthermore, our results indicate neither leptin nor insulin plays a critical role in the modulation of dopamine neurons regarding hedonic feeding behavior or anxiety-related behavior.

'Who does this patient belong to?' boundary work and the re/making of (NSTEMI) heart attack patients.

This ethnography within ten English and Welsh hospitals explores the significance of boundary work and the impacts of this work on the quality of care experienced by heart attack patients who have suspected non-ST segment elevation myocardial infarction (NSTEMI) /non-ST elevation acute coronary syndrome. Beginning with the initial identification and prioritisation of patients, boundary work informed negotiations over responsibility for patients, their transfer and admission to different wards, and their access to specific domains in order to receive diagnostic tests and treatment. In order to navigate boundaries successfully and for their clinical needs to be more easily recognised by staff, a patient needed to become a stable boundary object. Ongoing uncertainty in fixing their clinical classification, was a key reason why many NSTEMI patients faltered as boundary objects. Viewing NSTEMI patients as boundary objects helps to articulate the critical and ongoing process of classification and categorisation in the creation and maintenance of boundary objects. We show the essential, but hidden, role of boundary actors in making and re-making patients into boundary objects. Physical location was critical and the parallel processes of exclusion and restriction of boundary object status can lead to marginalisation of some patients and inequalities of care (A virtual abstract of this paper can be viewed at: https://www.youtube.com/channel/UC_979cmCmR9rLrKuD7z0ycA).

Methodological exemplar of integrating quantitative and qualitative evidence - supportive care for men with prostate cancer: what are the most important components?

AIMS: To present a methodological exemplar of integrating findings from a quantitative and qualitative review on the same topic to provide insight into components of care that contribute to supportive care that is acceptable to men with prostate cancer. BACKGROUND: Men with prostate cancer are likely to live a long time with the disease, experience side effects from treatment and therefore have ongoing supportive care needs. Quantitative and qualitative reviews have been published but the findings have yet to be integrated. DESIGN: Integration of quantitative and qualitative synthesized evidence. DATA SOURCE: Two previously published systematic reviews. REVIEW METHODS: Synthesized evidence on supportive care for men with prostate cancer was integrated from two previously published systematic reviews: a narrative quantitative review and a qualitative review with thematic synthesis. These two streams of synthesized evidence were synthesized using concurrent narrative summary. Data from both reviews were used to develop a set of propositions from which a summary of components of care that likely to contribute to supportive care acceptable to men with prostate cancer were identified. RESULTS: Nine propositions were developed which covered men's supportive care focusing on the role of health professionals. These propositions were used to compose nine components of care likely to lead to supportive care that is acceptable to men with prostate cancer. Some of these components are no/low cost such as developing a more empathic personalized approach, but more specific approaches need further investigation in randomized controlled trials, for example, online support. CONCLUSION: This methodological exemplar demonstrates the integration of quantitative and qualitative synthesized data to determine components of care likely to lead to provision of supportive care acceptable to men with prostate cancer.

Help-seeking amongst women survivors of domestic violence: a qualitative study of pathways towards formal and informal support.

BACKGROUND: Informal and formal support for women experiencing domestic violence and abuse (DVA) can improve safety and health outcomes. There has been little qualitative work on the role of both pathways to support and women's experiences of disclosing their experience of DVA in different contexts. OBJECTIVE AND STUDY DESIGN: This qualitative study used repeat interviews with women survivors of DVA to explore their pathways to support and their experiences of barriers and facilitators to disclosure and help-seeking. SETTING AND PARTICIPANTS: Thirty-one women seeking help from specialist DVA agencies in the UK were interviewed twice over 5 months. RESULTS: Women recounted long journeys of ambivalence, often only disclosing abuse after leaving the perpetrator. Access to specialist support rarely came via general practitioners, despite high levels of consulting for anxious and depressed feelings, and was more often facilitated by police or housing agencies following a crisis such as assault. Informal disclosure only led to specialist help if the family member or friend themselves had experience or knowledge of DVA. DISCUSSION AND CONCLUSIONS: Women experiencing DVA need earlier access to specialized DVA services. Many women needed an 'enabler' to facilitate access, but once this contact was made, disclosure to other professionals or to family and friends was legitimized in the eyes of the women. Safely accessible publicity about DVA services and an appropriate response from social and health-care professionals should be promoted, including support for women disclosing DVA to take action on the information they receive about services.

"Even 'Daily' is Not Enough": How Well Do We Measure Domestic Violence and Abuse?-A Think-Aloud Study of a Commonly Used Self-Report Scale.

This article explores the challenges of providing a quantitative measure of domestic violence and abuse (DVA), illustrated by the Composite Abuse Scale, a validated multidimensional measure of frequency and severity of abuse, used worldwide for prevalence studies and intervention trials. Cognitive "think-aloud" and qualitative interviewing with a sample of women who had experienced DVA revealed a tendency toward underreporting their experience of abuse, particularly of coercive control, threatening behavior, restrictions to freedom, and sexual abuse. Underreporting was linked to inconsistency and uncertainty in item interpretation and response, fear of answering truthfully, and unwillingness to identify with certain forms of abuse. Suggestions are made for rewording or reconceptualizing items and the inclusion of a distress scale to measure the individual impact of abuse. The importance of including qualitative methods in questionnaire design and in the interpretation of quantitative findings is highlighted.

Feasibility and impact of a computerised clinical decision support system on investigation and initial management of new onset chest pain: a mixed methods study.

BACKGROUND: Clinical decision support systems (CDSS) can modify clinician behaviour, yet the factors influencing their effect remain poorly understood. This study assesses the feasibility and acceptability of a CDSS supporting diagnostic and treatment decisions for patients with suspected stable angina. METHODS: Intervention The Optimising Management of Angina (OMA) programme includes a CDSS guiding investigation and medication decisions for clinicians managing patients with new onset stable angina, based on English national guidelines, introduced through an educational intervention. Design and participants A mixed methods study i. A study of outcomes among patients presenting with suspected angina in three chest pain clinics in England before and after introduction of the OMA programme. ii. Observations of clinic processes, interviews and a focus group with health professionals at two chest pain clinics after delivery of the OMA programme. OUTCOMES: Medication and cardiovascular imaging investigations undertaken within six months of presentation, and concordance of these with the recommendations of the CDSS. Thematic analysis of qualitative data to understand how the CDSS was used. RESULTS: Data were analysed for 285 patients attending chest pain clinics: 106 before and 179 after delivery of the OMA programme. 40 consultations were observed, 5 clinicians interviewed, and a focus group held after the intervention. The proportion of patients appropriate for diagnostic investigation who received one was 50 % (95 CI 34-66 %) of those before OMA and 59 % (95 CI 48-70 %) of those after OMA. Despite high use of the CDSS (84 % of consultations), observations and interviews revealed difficulty with data entry into the CDSS, and structural and practical barriers to its use. In the majority of cases the CDSS was not used to guide real-time decision making, only being consulted after the patient had left the room. CONCLUSIONS: The OMA CDSS for the management of chest pain is not feasible in its current form. The CDSS was not used to support decisions about the care of individual patients. A range of barriers to the use of the CDSS were identified, some are easily removed, such as insufficient capture of cardiovascular risk, while others are more deeply embedded in current practice, such as unavailability of some investigations or no prescribing privileges for nurses.

Optimizing Deep Brain Stimulation of the Nucleus Accumbens in a Reward Preference Rat Model.

OBJECTIVE/HYPOTHESIS: Deep brain stimulation (DBS) has become the preferred therapy for a growing number of treatment-resistant neuropsychiatric conditions, offering the benefit of being amenable to fine-tuning to enhance its efficacy. However, while some DBS parameters are routinely adjusted, the stimulation is almost always delivered in a continuous "tonic" pattern, which may be suboptimal at times. Our overall aim is to investigate the application of differing levels of rewarding DBS to the reconditioning of behavioral "trigger" and "non-trigger" stimuli in impulse-control disorders (including addiction). As a first step, we used a rat model of nucleus accumbens (NAc) DBS to rigorously compare the relative reward values of different stimulation paradigms. We hypothesized that delivering pulses in a more physiological pattern would prove more rewarding than delivering tonic stimulation. MATERIALS AND METHODS: We implanted microelectrodes in the left NAc shell and trained rats to initiate and terminate DBS to demonstrate their "preference" between different brain stimulation reward (BSR) paradigms. We tested a range of BSR paradigms, including tonic, intermittent tonic, and burst paradigms. Two paradigms were compared at a time, and paired t-tests were used to determine whether the rats significantly "preferred" one paradigm over another. RESULTS: The rats significantly preferred intermittent tonic BSR paradigms to continuous and burst paradigms, and generally preferred paradigms that delivered more pulses over the stimulation period. CONCLUSIONS: These findings highlight that the standard approach of delivering tonic DBS is not optimal under all circumstances. Further research should investigate which DBS paradigms are best for different brain disorders.

Chemogenetic Activation of RFRP Neurons Reduces LH Pulse Frequency in Female but not Male Mice.

Context: The neuropeptide RFRP-3 (RFamide-related peptide-3) is thought to play a role in the negative regulation of fertility. However, the exogenous administration of RFRP-3 yields varying results depending on the dose and route of administration, sex of the subject, and many other variables. Manipulation of in vivo neuronal activity using DREADDs (designer receptor exclusively activated by designer drugs) technology enables investigation of cell type-specific neuronal activation in a manner that better reflects endogenous neuronal activity. Objective: To test the effects of RFRP neuronal activation on pulsatile luteinizing hormone (LH) secretion. Methods: We generated mice expressing the stimulatory hM3Dq designer receptor exclusively in RFRP cells using 2 different Cre-loxP-mediated approaches: (1) we bred mice to express hM3Dq in all Rfrp-Cre-expressing cells, including some that transiently expressed Rfrp-Cre neonatally (RFRP × hM3Dq mice), and (2) we stereotaxically injected Cre-dependent hM3Dq into the dorsomedial nucleus of RFRP-Cre mice to drive hM3Dq expression exclusively in a subpopulation of adult Rfrp-Cre neurons (RFRP-AAV-hM3Dq mice). We then investigated the effects of acute hM3Dq activation on LH pulse frequency in RFRP × hM3Dq mice, RFRP-AAV-hM3Dq mice, and their respective controls. Results: In both female RFRP × hM3Dq and RFRP-AAV-hM3Dq mice, chemogenetic activation of Cre-driven hM3Dq led to a significant 35% to 50% reduction in LH pulse frequency compared with controls, while no differences in pulse amplitude or mean LH concentration were observed. In marked contrast, RFRP activation did not cause any changes to LH pulse dynamics in male mice. Conclusions: These data show for the first time that activation of neurons that have expressed Rfrp, or of a subset of adult RFRP neurons, can independently suppress LH pulsatility in female, but not male mice.

Cognitive Vulnerability to Mood Deterioration in an Exercise Cessation Paradigm.

Mood deterioration in response to exercise cessation is well-documented, but moderators of this effect remain unknown. This study tested the hypothesis that physically active individuals with higher levels of cognitive vulnerability (i.e., tendencies towards negative thought content and processes in response to stress or negative mood states) are at greater risk for increased anxiety and depressive symptoms when undergoing exercise cessation. Community adults meeting recommended physical activity guidelines (N=36) participated in a 4-week prospective, longitudinal study with 2 weeks each of maintained exercise and exercise cessation. Cognitive vulnerability measures included dysfunctional attitudes, brooding rumination, and cognitive reactivity (i.e., change in dysfunctional attitudes over a dysphoric mood induction). Anxiety and depression symptoms increased during exercise cessation. Brooding emerged as a risk factor for increases in Tension scores on the Profile of Mood States-Brief during exercise cessation. Future studies should explore brooding as a mediator (i.e., potential mechanism) of exercise-induced mood deterioration.

Leptin, but not Estradiol, Signaling in PACAP Neurons Modulates Puberty Onset.

The adipose-derived hormone leptin critically modulates reproductive function, such that its absence results in hypothalamic hypogonadism. Pituitary adenylate cyclase-activating polypeptide (PACAP)-expressing neurons are potential mediators of leptin's action on the neuroendocrine reproductive axis because they are leptin-sensitive and involved in both feeding behavior and reproductive function. In the complete absence of PACAP, male and female mice exhibit metabolic and reproductive abnormalities, yet there is some sexual dimorphism in the reproductive impairments. We tested whether PACAP neurons play a critical and/or sufficient role in mediating leptin's effects on reproductive function by generating PACAP-specific leptin receptor (LepR) knockout and rescue mice, respectively. We also generated PACAP-specific estrogen receptor alpha knockout mice to determine whether estradiol-dependent regulation of PACAP was critically involved in the control of reproductive function and whether it contributed to the sexually dimorphic effects of PACAP. We showed that LepR signaling in PACAP neurons is critically involved in the timing of female, but not male, puberty onset, but not fertility. Rescuing LepR-PACAP signaling in otherwise LepR-deficient mice was unable to rescue the reproductive deficits observed in LepR null mice but led to a marginal improvement in body weight and adiposity in females. Finally, PACAP-specific estrogen receptor alpha knockout did not lead to any changes in body weight or puberty onset compared with control mice. These data highlight that PACAP is a critical mediator of some of leptin's, but not estradiol's, influence on puberty onset in females, but is not critically involved in relaying leptin's effects in males or in adult females.

Deletion of Androgen Receptors From Kisspeptin Neurons Prevents PCOS Features in a Letrozole Mouse Model.

Polycystic ovarian syndrome (PCOS) is the leading cause of anovulatory infertility and is a heterogenous condition associated with a range of reproductive and metabolic impairments. While its etiology remains unclear, hyperandrogenism and impaired steroid negative feedback have been identified as key factors underpinning the development of PCOS-like features both clinically and in animal models. We tested the hypothesis that androgen signaling in kisspeptin-expressing neurons, which are key drivers of the neuroendocrine reproductive axis, is critically involved in PCOS pathogenesis. To this end, we used a previously validated letrozole (LET)-induced hyperandrogenic mouse model of PCOS in conjunction with Cre-lox technology to generate female mice exhibiting kisspeptin-specific deletion of androgen receptor (KARKO mice) to test whether LET-treated KARKO females are protected from the development of reproductive and metabolic PCOS-like features. LET-treated mice exhibited hyperandrogenism, and KARKO mice exhibited a significant reduction in the coexpression of kisspeptin and androgen receptor mRNA compared to controls. In support of our hypothesis, LET-treated KARKO mice exhibited improved estrous cyclicity, ovarian morphology, and insulin sensitivity in comparison to LET-treated control females. However, KARKO mice were not fully protected from the effects of LET-induced hyperandrogenism and still exhibited reduced corpora lutea numbers and increased body weight gain. These data indicate that increased androgen signaling in kisspeptin-expressing neurons plays a critical role in PCOS pathogenesis but highlight that other mechanisms are also involved.

Physiological regulation of leptin as an integrative signal of reproductive readiness.

Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function.

Central Irisin Signaling Is Required for Normal Timing of Puberty in Female Mice.

Timing of puberty requires exquisite coordination of genes, hormones, and brain circuitry. An increasing level of body adiposity, signaled to the brain via the fat-derived hormone leptin, is recognized as a major factor controlling puberty onset. However, it is clear that leptin is not the only metabolic cue regulating puberty, and that developmental regulation of this process also involves tissues other than adipose, with muscle development potentially playing a role in the timing of puberty. The proteolytic processing of fibronectin type 3 domain-containing protein 5 (FNDC5) releases a hormone, irisin. Irisin is primarily produced by muscle and is released into circulation, where levels increase dramatically as puberty approaches. We investigated the effects of a global deletion of the Fndc5 gene on pubertal timing. The absence of irisin induced a delay in puberty onset in female knockout mice compared with controls, without affecting body weight or gonadotropin-releasing hormone (GnRH) neuronal density. We next treated pre-pubertal wild-type male and female mice with an irisin receptor antagonist, cilengitide, for 7 days and observed a delay in first estrus occurrence compared to vehicle-treated control mice. Male puberty timing was unaffected. Next, we deleted the irisin receptor (integrin subunit alpha V) in all forebrain neurons and found a delay in the occurrence of first estrus in knockout females compared to controls. Taken together, these data suggest irisin plays a role in the timing of puberty onset in female mice via a centrally mediated mechanism.

Deletion of PTP1B From Brain Neurons Partly Protects Mice From Diet-Induced Obesity and Minimally Improves Fertility.

Reproductive dysfunction in women has been linked to high caloric diet (HCD)-feeding and obesity. Central resistance to leptin and insulin have been shown to accompany diet-induced infertility in rodent studies, and we have previously shown that deleting suppressor of cytokine signaling 3, which is a negative regulator of leptin signaling, from all forebrain neurons partially protects mice from HCD-induced infertility. In this study, we were interested in exploring the role of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of both leptin and insulin signaling, in the pathophysiology of HCD-induced obesity and infertility. To this end, we generated male and female neuron-specific PTP1B knockout mice and compared their body weight gain, food intake, glucose tolerance, and fertility relative to control littermates under both normal calorie diet and HCD feeding conditions. Both male and female mice with neuronal PTP1B deletion exhibited slower body weight gain in response to HCD feeding, yet only male knockout mice exhibited improved glucose tolerance compared with controls. Neuronal PTP1B deletion improved the time to first litter in HCD-fed mice but did not protect female mice from eventual HCD-induced infertility. While the mice fed a normal caloric diet remained fertile throughout the 150-day period of assessment, HCD-fed females became infertile after producing only a single litter, regardless of their genotype. These data show that neuronal PTP1B deletion is able to partially protect mice from HCD-induced obesity but is not a critical mediator of HCD-induced infertility.