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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. Navitoclax 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. 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.