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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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 the authors.)

The gastrointestinal disease of ruminants is clinically known as Johne's disease (JD) and is caused by Mycobacterium avium subspecies paratuberculosis (MAP). An accumulative effect by insensitive diagnostic tools, a long subclinical stage of infection, and lack of effective vaccines have made the control of JD difficult. Currently lacking in the model systems of JD are undefined correlates of protection and the sources of inflammation due to JD. As an alternative to commonly studied immune responses, such as the Th1/Th2 paradigm, a non-classical Th17 immune response to MAP has been suggested. Indeed MAP antigens induce mRNAs encoding the Th17-associated cytokines IL-17A, IL-17F, IL-22, IL-23, IL-27, and IFNγ in CD3+ T cell cultures as determined by RT-qPCR. Although not as robust as when cultured with monocyte-derived macrophages (MDMs), MAP is able to stimulate the upregulation of these cytokines from sorted CD3+ T cells in the absence of antigen-presenting cells (APCs). CD4+ and CD8+ T cells are the main contributors of IL-17A and IL-22 in the absence of APCs. However, MAP-stimulated MDMs are the main contributor of IL-23. In vivo , JD+ cows have more circulating IL-23 than JD- cows, suggesting that this proinflammatory cytokine may be important in the etiology of JD. Our data in this study continue to suggest that Th17-like cells and associated cytokines may indeed play an important role in the immune responses to MAP infection and the development or control of JD., (Copyright © 2020 DeKuiper, Cooperider, Lubben, Ancel and Coussens.)