Endocrinology

The circadian clock is a biological time-keeping system to govern temporal rhythms of the endocrine system and metabolism. The master pacemaker of biological rhythms is housed in the hypothalamic suprachiasmatic nucleus (SCN) where approximately 20,000 neurons exist and receive light stimulus as a predominant timed external cue (zeitgeber). The central SCN clock orchestrates molecular clock rhythms in peripheral tissues and coordinates circadian metabolic homeostasis at a systemic level. Accumulated evidence underscores an intertwined relationship between the circadian clock system and metabolism: the circadian clock provides daily dynamics of metabolic activity whereas the circadian clock activity is modulated by metabolic and epigenetic mechanisms...

Corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) are central to the stress response. Chemogenetic activation of PVN CRH neurons decreases LH pulse frequency but the mechanism is unknown. In the present study, optogenetic stimulation of PVN CRH neurons suppressed LH pulse frequency in estradiol (E2)-replaced ovariectomised (OVX) CRH-cre mice and this effect was augmented or attenuated by intra-PVN GABAA or GABAB receptor antagonism respectively. PVN CRH neurons signal to local GABA neurons which may provide a possible indirect mechanism by which PVN CRH neurons suppress LH pulse frequency...

Hyperprolactinemia is prevalent in up to 16% of the infertile males. Although prolactin receptor (PRLR) is present on various testicular cells, the physiological role of this receptor in spermatogenesis remains elusive. The aim of this study is to delineate prolactin actions in rat testicular tissue. Serum prolactin, developmental expression of PRLR, signaling pathways associated, and gene transcription regulation in the testes were investigated. Serum prolactin and testicular PRLR expression was found to be significantly increased at pubertal and adult age as compared to pre-pubertal...

Lipid metabolism is tightly linked to adiposity. Prader-Willi syndrome (PWS) is a typical genetic disorder caused obesity, however, the distinct lipidomic profiles in PWS children have not been thoroughly investigated. Herein, serum lipidomics analysis were simultaneously explored in PWS, simple obesity (SO) and normal children (Normal). Results indicated that the total concentration of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in PWS group were significantly deceased in comparison with both SO and Normal group...

Steroid hormone signaling pathways are critical for organismal development and act through binding to nuclear receptors driving transcriptional regulation. In this review, we summarize evidence for another - underrated - mechanism of action for steroid hormones: their ability to modulate the alternative splicing of pre-mRNA. Thirty years ago, pioneering studies used in vitro transfection of plasmids expressing alternative exons under the control of hormone responsive promoters in cell lines. These studies demonstrated that steroid hormone binding to their nuclear receptor impacted both gene transcription and alternative splicing outcomes...

Corticosteroids act on the glucocorticoid receptor (GR; NR3C1) to resolve inflammation and are routinely prescribed to breast cancer patients undergoing chemotherapy treatment to alleviate side effects. Triple negative breast cancers (TNBCs) account for 15-20% of diagnoses and lack expression of estrogen and progesterone receptors as well as amplified HER2, but often express high GR levels. GR is a mediator of TNBC progression to advanced metastatic disease, however the mechanisms underpinning this transition to more aggressive behavior remain elusive...

Endometriosis is an estrogen-dependent disorder defined as the deposition and growth of endometrial tissue outside the uterus, including but not limited to the pelvic peritoneum, rectovaginal septum, and ovaries. Endometriosis is a significant contributor to pelvic pain and subfertility and has been associated with an increased incidence of certain cancers, including ovarian. Appropriate treatment of endometriosis can reduce morbidity, but generally is only used to address symptoms, since no cure currently exists...

Pre-menopausal women have a lower incidence of cardiovascular disease (CVD) compared to their age-matched male counterparts however this discrepancy is abolished following the transition to menopause or during low estrogen states. This, combined with a large amount of basic and preclinical data indicating that estrogen is vasculoprotective, supports the concept that hormone therapy could improve cardiovascular health. However, clinical outcomes in individuals undergoing estrogen treatment have been highly variable, challenging the current paradigm regarding the role of estrogen in the fight against heart disease...

Alpha-ketoglutarate (α-KG)-dependent dioxygenases are a superfamily of enzymes that require oxygen, reduced iron and α-ketoglutarate for their catalytic functions. Therefore, they have the potential to sense the availabilities of oxygen, iron and specific metabolites, including α-KG and its structurally related metabolites. These enzymes play essential roles in various biological processes, including cellular adaptation to hypoxia, epigenetic and epitranscriptomic regulation of gene expression, and metabolic reprogramming...

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell types...

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...

The pituitary gland regulates growth, metabolism, reproduction, the stress response, uterine contractions, lactation, and water retention. It secretes hormones in response to hypothalamic input, end organ feedback, and diurnal cues. The mechanisms by which pituitary stem cells are recruited to proliferate, maintain quiescence or differentiate into specific cell types, especially thyrotropes, are not well understood. We utilized single-cell RNA sequencing in juvenile P7 mouse pituitary cells to identify novel factors in pituitary cell populations, with a focus on thyrotropes and rare subtypes...

Approximately 70% of human breast cancers express estrogen receptor-α (ERα), providing a potential target for endocrine therapy. However, 30%-40% of patients with ER+ breast cancer still experiences recurrence and metastasis, with a 5-year relative overall survival rate of 24%. In this study, we identified NAMPT, an important enzyme in nicotinamide adenine dinucleotide (NAD+) metabolism, to be increased in metastatic breast cancer (MBC) cells treated with Fulv. We tested whether the blockade of NAD+ production via inhibition of nicotinamide phosphoribosyltransferase (NAMPT) synergizes with standard-of-care therapies for ER+ metastatic breast cancer in vitro and in vivo...

Despite the importance of the mouse in biomedical research, the levels of circulating gonadal steroids across the estrous cycle are not established with any temporal precision. Using liquid chromatography-mass spectrometry, now considered the gold standard for steroid hormone analysis, we aimed to generate a detailed profile of gonadal steroid levels across the estrous cycle of C57BL/6J mice. For reference, luteinizing hormone (LH) and prolactin concentrations were measured in the same samples by sandwich ELISA...

The androgen receptor (AR) is one of the oldest therapeutic targets in oncology and continues to dominate the treatment landscape for advanced prostate cancer, where nearly all treatment regimens include some form of AR modulation. In this regard, AR remains the central driver of prostate cancer cell biology. Emerging preclinical and clinical data implicate key roles for AR in additional cancer types, thereby expanding the importance of this drug target beyond prostate cancer. In this mini-review, new roles for AR in other cancer types are discussed as well as their potential for treatment with AR-targeted agents...

REV-ERB nuclear receptors are potent transcriptional repressors that play an important role in the core mammalian molecular clock and metabolism. Deletion of both REV-ERBα and its largely redundant isoform REV-ERBβ in a murine tissue-specific manner have shed light on their specific functions in clock mechanisms and circadian metabolism. This review highlights recent findings that establish REV-ERBs as crucial circadian timekeepers in a variety of tissues, regulating overlapping and distinct processes that maintain normal physiology and protect from metabolic dysfunction...

Protein intake potently increases body temperature and energy expenditure, but the underlying mechanism thereof remains incompletely understood. Simultaneously, protein intake potently stimulates glucagon-like peptide-1 (GLP-1) secretion. Here, we examined the involvement of GLP-1 in the thermic effects of dietary proteins in rodents by measuring rectal temperature and energy expenditure and modulating GLP-1 signaling. Rectal temperature of rats or mice fasted for 4 or 5 h were measured using a thermocouple thermometer before and after an oral administration of nutrients...

Instructive signals that delineate the formation of thyroid follicles by TSH in stem cells are complex. Here, we have examined the role of protein kinase C (PKC) by using a unique Gαq/11 biased small molecule (MSq1) to develop thyroid progenitor cells. Mouse embryonic stem cells (mESCs) were differentiated into anterior endoderm cells and treated with either TSH or MSq1 in the presence or absence of PKC inhibitors. The transcriptional and translational response of key thyroid markers - NIS, TG and TSHR as well as potential signaling molecules, were then analyzed...

One of the common mechanisms responsible for obstetric complications, affecting millions of women every year, is abnormal uterine contractility. Despite the critical importance of this process for women's health, mechanisms of uterine contraction regulation remain poorly understood. The initiation of uterine smooth muscle (myometrial) contraction is an inflammatory process, accompanied by upregulation of pro-inflammatory genes and cytokine release. In this study, we show that sphingolipid metabolism is activated during human labor and that sphingosine 1-phosphate (S1P), the main bioactive sphingolipid, may modify the myometrial pro-inflammatory phenotype...

Muscle atrophy is the cause and consequence of obesity. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum (ER) stress and insulin resistance in the liver and adipose tissues. However, obesity-associated regulation of proteasome function and its role in the skeletal muscles remains under-investigated. Here, we established skeletal muscle-specific 20S proteasome assembly chaperone-1 (PAC1) knockout (mPAC1KO) mice. A high-fat diet (HFD) activated proteasome function by ∼8 fold in the skeletal muscles, which was reduced by 50% in mPAC1KO mice...