Hertzosborne5986

Either physical damage or being born with a specific genetic abnormality can impact on the functioning of the hypothalamus, resulting in diverse physical manifestations and/or specific behavior disorders. The impact of physical damage due to craniopharyngioma (CP) and/or surgery to remove a craniopharyngioma is compared and contrasted with the impact resulting from the genetic abnormalities associated with Prader-Willi syndrome (PWS). Similarities between PWS and CP posttreatment include hyperphagia and weight gain, low growth hormone levels, low bone density in adults, hypogonadism, disturbed temperature regulation, disturbed sleep and daytime sleepiness, memory difficulties, and problems with behavior and with peer relationships. These disturbances are an indication of the hypothalamus's central role in homeostasis. Most of the abnormalities appear to be more severe postoperatively in people with CP. Differences include higher ghrelin levels in PWS, complete absence of pituitary hormones in many cases of CP, higher incidence of thyroid dysfunction in CP, "growth without growth hormone" in obese children with CP, different types of diabetes (diabetes insipidus in CP and diabetes mellitus in PWS), and evidence of developmental delay and low IQ in people with PWS.Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, arising from a loss of paternity expressed genetic material on the imprinted chromosome locus 15q11-q13. Despite increasing clarity on the underlying genetic defects, the molecular basis of the condition remains poorly understood. Hypothalamic dysfunction is widely recognized as the basis of the core symptoms of PWS, which include a deficiency in growth hormone and reproductive hormones, circadian rhythm abnormalities, and a lack of satiety, leading to an extreme obesity, among others. Genome-wide gene expression analysis (transcriptomics) offers an unbiased interrogation of complex disease pathogenesis and a potential window into the dysregulated pathways involved in disease. In this chapter, we review the findings from recent work investigating the PWS hypothalamic transcriptome, discuss the significance of the findings in relation to the clinical presentation and molecular underpinnings of PWS, and highlight future research directions.Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder linked to the lack of expression of specific maternally imprinted genes located in the chromosomal region 15q11-q13. Impaired hypothalamic development and function explain most of the phenotype that is characterized by a specific trajectory from anorexia at birth to excessive weight gain at later ages, which is accompanied by hyperphagia and early severe obesity, as well as by other hormonal deficiencies, behavioral deficits, and dysautonomia. In almost all patients, their endocrine dysfunction involves growth hormone deficiency and hypogonadism, which originate from a combination of both peripheral and hypothalamic origin, central hypothyroidism in 40%, precocious adrenarche in 30% of the cases, and in rare cases, also adrenocorticotropin deficiency and precocious puberty. In addition, the oxytocin (OXT) and ghrelin systems are impaired in most patients and involved in a poor suckling response at birth, and hyperphagia with food addiction, poor social skills, and emotional dysregulation. Current hormonal replacement treatments are the same as used in classical hormonal deficiencies, and recombinant human GH treatment is registered since 2000 and has dramatically changed the phenotype of these children. OXT and OXT analogue treatments are currently investigated as well as new molecules targeting the ghrelin system. The severe condition of PWS can be seen as a model to improve the fine description and treatments of hypothalamic dysfunction.The hypothalamus, which is part of the brain of all vertebrate animals, is considered the link between the central nervous system (CNS) and (i) the endocrine system via the pituitary gland and (ii) with our organs via the autonomic nervous system. It synthesizes and releases neurohormones, which in turn stimulate or inhibit the secretion of other hormones within the CNS, and sends and receives signals to and from the peripheral nervous and endocrine systems. As the brain region responsible for energy homeostasis, the hypothalamus is the key regulator of thermoregulation, hunger and satiety, circadian rhythms, sleep and fatigue, memory and learning, arousal and reproductive cycling, blood pressure, and heart rate and thus orchestrates complex physiological responses in order to maintain metabolic homeostasis. These critical roles implicate the hypothalamus in neuroendocrine disorders such as obesity, diabetes, anorexia nervosa, bulimia, and others. In this chapter, we focus on the use of human-induced pluripotent stem cells (hiPSCs) and their differentiation into hypothalamic neurons in order to model neuroendocrine disorders such as extreme obesity in a dish. To do so, we discuss important steps of human hypothalamus development, neuroendocrine diseases related to the hypothalamus, multiple protocols to differentiate hiPSCs into hypothalamic neurons, and severe obesity modeling in vitro using hiPSCs-derived hypothalamic neurons.Energy balance is centrally regulated by the brain through several interacting neuronal systems involving external, peripheral, and central factors within the brain. The hypothalamus integrates these factors and is the key brain area in the regulation of energy balance. In this review, we will explain the structure of the hypothalamus and its role in the regulation of energy balance. An important part of energy balance regulation is the sensing of nutrient status and availability. This review will focus on the sensing of the two main sources of energy by the hypothalamus glucose and fat. As many common health problems and chronic diseases can be traced back to a disrupted hypothalamic function, we will also discuss hypothalamic sensing of glucose and fats in these pathologies. Finally, we will summarize the current knowledge and discuss how this may be applied clinically and for future research perspectives.Over the past decade, hypothalamic microinflammation has been studied and appreciated as a core mechanism involved in the advancement of metabolic syndrome and aging. Accumulating evidence suggests that atypical microinflammatory insults disturb hypothalamic regulation resulting in metabolic imbalance and aging progression, establishing a common causality for these two pathophysiologic statuses. Studies have causally linked these changes to activation of key proinflammatory pathways, especially NF-κB signaling within the hypothalamus, which leads to hypothalamic neuronal dysregulation, astrogliosis, microgliosis, and loss of adult hypothalamic neural stem/progenitor cells. While hypothalamic microinflammation is a complex, multifaceted process, initial work has been done to reveal how it contributes to the pathogenesis of metabolic syndrome and aging, and studies inhibiting hypothalamic microinflammation through targeting proinflammatory signaling pathways have shown to be beneficial against these disorders and diseases. In this chapter, we provide a broad overview on hypothalamic microinflammation, focusing on its features, inducers, and shared pathogenic roles in metabolic syndrome and aging.Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.Empty sella is a pituitary disorder characterized by the herniation of the subarachnoid space within the sella turcica. This is often associated with a variable degree of flattening of the pituitary gland. Empty sella has to be distinguished in primary and secondary forms. Primary empty sella (PES) excludes any history of previous pituitary pathologies such as previous surgical, pharmacologic, or radiotherapy treatment of the sellar region. PES is considered an idiopathic disease and may be associated with idiopathic intracranial hypertension. Secondary empty sella, however, may occur after the treatment of pituitary tumors through neurosurgery or drugs or radiotherapy, after spontaneous necrosis (ischemia or hemorrhage) of chiefly adenomas, after pituitary infectious processes, pituitary autoimmune diseases, or brain trauma. Empty sella, in the majority of cases, is only a neuroradiological finding, without any clinical implication. However, empty sella syndrome is defined in the presence of pituitary hormonal dysfunction (more frequently hypopituitarism) and/or neurological symptoms due to the possible coexisting of idiopathic intracranial hypertension. Empty sella syndrome represents a peculiar clinical entity, characterized by heterogeneity both in clinical manifestations and in hormonal alterations, sometimes reaching severe extremes. Y-27632 mouse For a proper diagnosis, management, and follow-up of empty sella syndrome, a multidisciplinary approach with the integration of endocrine, neurological, and ophthalmological experts is strongly advocated.Nocturnal enuresis is the involuntary pass of urine during sleep beyond the age of 5 years. It is a common condition in childhood and has an impact on the child's well-being. Research into the pathophysiology of the condition in the last decades has led to a paradigm shift, and enuresis is no longer considered a psychiatric disorder but rather a maturation defect with a somatic background. An excess urine production during sleep is a common finding in children with enuresis and disturbances in the circadian rhythm of arginine-vasopressin (AVP) is found in the majority of children with nocturnal polyuria. Children with enuresis and nocturnal polyuria lack the physiologic increase in AVP levels during sleep and treatment with the AVP analogue desmopressin can restore this rhythm and lead to dry nights. The reasons for this aberrant circadian AVP rhythm are not established. Furthermore, not all children with enuresis and nocturnal polyuria can be successfully treated with desmopressin suggesting that factors beyond renal water handling can be implicated such as natriuresis, hypercalciuria, and sleep-disordered breathing.