Molecular and Cellular Bases of Lipodystrophy Syndromes

Lipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed.

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

Clinical Characteristics of Primary Hypophysitis – A Single-Centre Series of 60 Cases

Objective Clinical data on primary hypophysitis are still scarce. Especially non-surgical cases are underreported. We sought to analyse clinical characteristics of primary hypophysitis, particularly in clinically diagnosed patients. Design Retrospective single centre study in 60 patients with primary hypophysitis. Methods Symptoms, MRI, histopathological findings, treatment and outcomes were analysed in 12 histopathologically and 48 clinically diagnosed patients. Diagnostic criteria for clinical diagnosis were: a) MRI findings compatible with primary hypophysitis; b) course of disease excluding other differential diagnoses. Mean duration of follow-up was 69 months. Results Female sex was predominant (73%). Fatigue (52%), headache (38%) and diabetes insipidus (38%) were the most frequent symptoms. 42% had a concomitant autoimmune disease. The corticotropic, thyrotropic, gonadotropic, somatotropic axis was impaired in 67%, 57%, 52%, 20%, respectively. Men had a higher number of impaired hormone axes (p=0.022) with the gonadotropic axis being affected more frequently in men (p=0.001). Infundibular thickening (56%) and space occupying lesions (46%) were typical MRI findings. Pituitary size was frequently enlarged at presentation (37%) but diminished during observation (p=0.029). Histopathologically and clinically diagnosed cases did not differ. Conclusions The cohort of clinically diagnosed patients did not differ from our histopathologically diagnosed patients or from published cohorts with predominantly surgical patients. Thus, diagnosis of primary hypophysitis using clinical criteria seems feasible.

Origin and Evolution of the Neuroendocrine Control of Reproduction in Vertebrates, With Special Focus on Genome and Gene Duplications

In humans, as in the other mammals, the neuroendocrine control of reproduction is ensured by the brain-pituitary gonadotropic axis. Multiple internal and environmental cues are integrated via brain neuronal networks, ultimately leading to the modulation of the activity of gonadotropin-releasing hormone (GnRH) neurons. The decapeptide GnRH is released into the hypothalamic-hypophysial portal blood system and stimulates the production of pituitary glycoprotein hormones, the two gonadotropins luteinizing hormone and follicle-stimulating hormone. A novel actor, the neuropeptide kisspeptin, acting upstream of GnRH, has attracted increasing attention in recent years. Other neuropeptides, such as gonadotropin-inhibiting hormone/RF-amide related peptide, and other members of the RF-amide peptide superfamily, as well as various nonpeptidic neuromediators such as dopamine and serotonin also provide a large panel of stimulatory or inhibitory regulators. This paper addresses the origin and evolution of the vertebrate gonadotropic axis. Brain-pituitary neuroendocrine axes are typical of vertebrates, the pituitary gland, mediator and amplifier of brain control on peripheral organs, being a vertebrate innovation. The paper reviews, from molecular and functional perspectives, the evolution across vertebrate radiation of some key actors of the vertebrate neuroendocrine control of reproduction and traces back their origin along the vertebrate lineage and in other metazoa before the emergence of vertebrates. A focus is given on how gene duplications, resulting from either local events or from whole genome duplication events, and followed by paralogous gene loss or conservation, might have shaped the evolutionary scenarios of current families of key actors of the gonadotropic axis.

The Involvement of Hormones in Fish: Basic and Applied Aspects of Russian Sturgeon (Acipenser Gueldenstaedtii)

Fish are a very large group, containing a huge variety of over 33,000 species.Scientific knowledge about the interaction between hormones of the somatic axis (SA) and the gonadotropic axis (GA), both of which function in the brain, and the pituitary gonad axis (BPG) that controls growth and reproduction, is vital for the domestication of fish in aquaculture.The Acipenserida family comprises 27 species, some of which have a very high economic value, among them Russian sturgeon (Acipenser gueldenstaedtii) that adapted to growth in aquaculture conditions. Many aspects aimed at improving the adaptation and production of Russian sturgeon (Acipenser gueldenstaedtii) have been studied for quite a long time. Models based on the results of our and others’ studies describing the interaction between GA and SA during oogenesis in Russian sturgeon have been suggested. The mRNA relative level of FSH during vitellogenesis (VTL) was higher in females than in males, affecting VTL secretion of vitellogenin (Vg); however, it was lower in the pre-vitellogenic stage than in VTL. No difference was found in mRNA levels of the luteinizing hormone (LH) in Russian sturgeon during the first four years of growth. During its first five years of growth, the level of GH mRNA was higher in females than in males, but due to the high standard deviation of the mean, the difference was not significant. IGF-I mRNA expression differed between the various tissues.

Neuroendocrine Mechanisms Involved in Male Sexual and Emotional Behavior

Objective:The aim of this narrative review was to analyze the role played by brain areas, neurohormones and neurotransmitters in the regulation of emotional and sexual behavior in the male.Methods:We analyzed the currently available literature dealing with brain structures, neurotransmitters and neurohormones involved in the regulation of emotional and sexual behavior in the male.Results:A common brain pathway is involved in these two aspects. The Hippocampus seems to control the signals coming from the external environment, while the amygdala and the hypothalamus control the response to social stimuli. Stimulation of amygdala in the animal models increases sexual performance, while it triggers violent emotional responses. Stimulation of the hypothalamus causes reactions of violent anger and increases sexual activity. Catecholaminergic stimulation of the amygdala and hypothalamus increases emotional and sexual behavior, while serotonin plays an inhibitory role. Cholinergic inhibition leads to a suppression of copulatory activity, while the animal becomes hyperemotive. Opioids, such as β-endorphin and met-enkephalin, reduce copulatory activity and induce impotence. Gonadal steroid hormones, such as estrogen in female and testosterone in male, which play a major role in the control of sexual behavior and gender difference have been highlighted in this review. Vasopressin, oxytocin and their receptors are expressed in high density in the “social behavior neural network” and play a role as signal system controlling social behavior. Finally, the neuropeptide kisspeptin and its receptors, located in the limbic structures, mediate olfactory control of the gonadotropic axis.Conclusion:Further studies are needed to evaluate possible implications in the treatment of psychosexual and reproductive disorders.