The hypothalamus periodically releases GnRH to control the reproductive axis activity. Under the action of GnRH, the pituitary pulsatile releases gonadotropin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) into the blood. These hormones then induce the gonad to produce a variety of hormones, such as estradiol, progesterone, inhibin, and testosterone, which all play important roles in reproductive regulation.

Gonadotropin-releasing hormone (GnRH) is a key factor on the hypothalamic-pituitary-gonad (HPG) axis of vertebrates, which plays an important role in the development and maturation and reproduction of gonads of vertebrates. Using the zebrafish model, the Institute of Hydrobiology, the Chinese Academy of Sciences has for the first time discovered a new function of GnRH3 neuropeptide and its mechanism of action.

Using gene editing technology, Hu Wei, a researcher at the Institute of Hydrology, constructed a zebrafish model with a GnRH3 mutation, and found that zebrafish with GnRH3 knockout had partial male development, and the proportion of adult males increased significantly. Studies have shown that the number of primordial germ cells (PGCs) in early embryos before the sphere period of GnRH3 mutant zebrafish is not significantly different from that of wild type, but the number of mutant PGCs is significantly lower than that of wild type in subsequent developmental stages. Analysis of the proliferation and migration of zebrafish PGCs revealed that after GnRH3 mutation, PGCs could migrate normally, but their proliferation was significantly affected. Further research revealed that GnRH3 regulates the proliferation of early embryonic zebrafish PGCs through MAPK signaling pathways, and at the same time regulates the expression of genes related to female and male glandular cells in the critical period of zebrafish early sex differentiation, and then further affects zebrafish’s sex differentiation. This is the first time that GnRH3 has been found to play an important role in the proliferation and sex differentiation of PGCs in early zebrafish embryonic development.

This is remarkable and the relevant findings were recently published online in Endocrinology.

Gonadotropin Releasing Hormone Analogs

GnRH agonists and antagonists are both synthetic analogs of the GnRH peptide hormone. Through shutting down the GnRH-mediated release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, castrate testosterone levels can be achieved. In contrast, GnRH antagonists achieve this effect through direct blockade of the GnRH receptor. Simply put it, GnRH agonists function through their interruption of the normal pulsatile signaling of physiologic GnRH. Persistent elevation of GnRH agonist activity leads to downregulation of the GnRH receptor, thereby causing decreased levels of LH, FSH, and testosterone. 1,2 GnRH agonists often cause an initial surge in LH, FSH, and testosterone before this downregulation occurs. In contrast, GnRH antagonists do not cause this androgen surge. Available GnRH agonists include leuprolide, goserelin, and triptorelin. Available GnRH antagonists include abarelix and degarelix.

Reference:

1. Ke Feng, Xuefan Cui, Yanlong Song, Binbin Tao, Ji Chen, Jing Wang, Shaojun Liu, Yonghua Sun, Zuoyan Zhu, Vance L Trudeau, Wei Hu.(2019). Gnrh3 regulates PGC proliferation and sex differentiation in developing zebrafish. Endocrinology.
2. BSBrock R.Baker, BSJahan J.Mohiuddin, MD, MPHRonald C.Chen, Prostate Cancer (Second Edition), Science and Clinical Practice 2016, Pages 387-398.

Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar) or when the body cannot effectively utilize the insulin it produces. Diabetes mellitus can be classified into two main types: type 1 (previously known as insulin-dependent) and type 2 (formerly called non-insulin-dependent or adult-onset). Type 1 diabetes was characterized by absolutely lack of the production and secretion of insulin, due to destruction of the insulin producing pancreatic β-cells. Patients with type I diabetes require daily administration of insulin. Type 2 Diabetes, which was characterized by insulin resistance and the body’s inability to secrete enough insulin. 90% of diabetes cases belong to this type.

Obesity is associated with numerous co-morbidities and any treatment for obesity is likely to be required long term; the therapeutic window of any new pharmacotherapy must therefore be closely scrutinized before approval. The classical neurotransmitter and endocannabinoid systems are widespread within the CNS, reflecting multiple physiological roles, and manipulation of these systems carries the risk of unwanted effects. Neuropeptides can act in the CNS as neuromodulators of the classical neurotransmitter systems. Typically expressed by discrete clusters of neurons, they project diffusely throughout the CNS, and modulate postsynaptic neurons in a way that can alter their responses to classical neurotransmitters. All CNS neurons that produce neuromodulators also release classical neurotransmitters, for example, neuropeptide Y (NPY) and galanin regulate central adrenergic transmission within the hypothalamus.

Levels of circulating spexin, a newly identified neuropeptide, decrease with age and may predict risk for obesity and diabetes, according to findings from a cross-sectional study of healthy Chinese women. Research suggests that spexin is associated with satiety, gastrointestinal motility, energy metabolism, and glucose and lipid metabolism. Several animal studies have investigated the biological functions of spexin in fish and rodents; however, the clinical significance of the neuropeptide remains largely unknown.

Zhao-xiang Bian, MD, PhD, director of the Hong Kong Chinese Medicine Clinical Study Centre at Hong Kong Baptist University, China, and colleagues analyzed data from 68 women recruited from the clinical division at the School of Chinese Medicine at Hong Kong Baptist University (median age, 39 years; median BMI, 20.5 kg/m²). Researchers measured serum spexin levels via an enzyme-linked immunosorbent assay, as well as fasting glucose, total cholesterol, triglycerides, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine. Researchers stratified participants by spexin tertiles and performed two-way analysis of variance (ANOVA) to test the main and interaction effects of age and spexin on BMI, fasting glucose and triglycerides.

“In healthy women, circulating spexin levels decrease with age and negatively correlate with BMI, fasting glucose and triglycerides,” Bian said. “Meanwhile, no interaction effects of spexin and age on BMI and fasting glucose were found. Spexin may independently predict the risk of high BMI and high fasting glucose.” Bian said the close correlation between spexin and age suggests the possible role of the peptide in aging-related functions and disorders, which need to be further explored by additional clinical studies and mechanistic investigations to elucidate the role of spexin in aging.