Hypothalamic microinflammation.

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.

Regulation of muscle and metabolic physiology by hypothalamic erythropoietin independently of its peripheral action.

OBJECTIVE: The glycoprotein hormone erythropoietin (EPO) is required for erythropoiesis, and the kidney is the primary site of adult EPO synthesis. Limited evidence has suggested that EPO could be detectable in the brain under certain conditions, but it remains unknown if the brain might have its own EPO system for biological functions that are independent of peripheral EPO production and action. We performed this study to address this question using mice under normal conditions versus pathophysiological conditions including aging and dietary obesity. METHODS: EPO expression was measured in different brain regions as well as in the cerebrospinal fluid. Hypothalamic ventricular EPO was administered to physiologically examine possible therapeutic effects on the conditions of aging and dietary obesity. Body weight, body composition, insulin tolerance, and glucose tolerance were measured to assess the central effects of EPO on metabolic physiology, and muscle strength and histology were analyzed to assess the central effects of EPO on muscle function. In addition, ß2-adrenergic receptor knockout bone marrow transplant was employed to determine the potential role of bone marrow in linking the brain to some of these peripheral functions. RESULTS: This study revealed that EPO is expressed in the ventromedial hypothalamus in addition to a few other brain regions and is present in the cerebrospinal fluid. Unlike blood EPO concentration, which increased with aging and dietary obesity, hypothalamic EPO decreased in these disease conditions. Therapeutically, aged mice were chronically treated with EPO in the hypothalamic ventricle, showing an increase in lean mass, while body weight and fat mass decreased as a result of a moderate reduction of food intake. Both muscle and metabolic functions were improved by this central treatment, and mechanistically, adrenergic signals to the bone marrow played a role in conveying hypothalamic EPO to these peripheral actions. Dietary obesity was also studied, showing that hypothalamic EPO treatment caused a reduction in food intake and obesity, leading to improved metabolic functions related to decreased fat as well as increased lean mass. CONCLUSIONS: Hypothalamic EPO plays a role in the central regulation of muscle and metabolic physiology, while its decline contributes to aging and obesity physiology in a manner that is independent of peripheral EPO.

"Hypothalamic Microinflammation" Paradigm in Aging and Metabolic Diseases.

Under conditions leading to aging and metabolic syndrome, the hypothalamus atypically undergoes proinflammatory signaling activation leading to a chronic and stable background inflammation, referred to as "hypothalamic microinflammation." Through the past decade of research, progress has been made to causally link this hypothalamic inflammation to the mechanism of aging as well as metabolic syndrome, promoting the "hypothalamic microinflammation" theory, which helps characterize the consensus of these epidemic health problems. In general, it is consistently appreciated that hypothalamic microinflammation emerges during the early stages of aging and metabolic syndrome and evolves to be multifaceted and advanced alongside disease progression, while inhibition of key inflammatory components in the hypothalamus has a broad range of effects in counteracting these disorders. Herein, focusing on aging and metabolic syndrome, this writing aims to provide an overview of and insights into the mediators, signaling components, cellular impacts, and physiological significance of this hypothalamic microinflammation.

Age-dependent decline of hypothalamic HIF2α in response to insulin and its contribution to advanced age-associated metabolic disorders in mice.

Hypoxia-inducible factor-2α (HIF2α) is a nuclear transcription factor that plays a critical role in cell survival including metabolic adaptation under hypoxia as well as normoxia, but whether HIF2α contributes to the control of whole-body metabolic balance is unclear. In this study, we found that the hypothalamic HIF2α protein level rapidly increases in young mice that are centrally stimulated with insulin. However, this insulin-induced HIF2α up-regulation is substantially attenuated in mice of advanced age. This attenuation is comparable with the effect of high-calorie feeding in young mice. Of note, unlike high-calorie feeding conditions, age-dependent HIF2α attenuation occurs without impaired activation of the hypothalamic IR/IRS-2/AKT/FOXO1 pathway in response to insulin. Molecular and physiological analyses revealed that hypothalamic HIF2α contributes to the action of central insulin in regulation of proopiomelanocortin (Pomc) gene expression and food intake. HIF2α knockout in POMC neurons led to age-dependent excess weight gain and fat increase, a phenotype that was associated with a mild degree of glucose intolerance and insulin resistance. In conclusion, hypothalamic HIF2α responds to insulin, and the up-regulation is involved in adaptive metabolic regulation as age increases, whereas impairment of HIF2α in the hypothalamus contributes to weight gain and glucose disorders in age-dependent manners.

Hypothalamic and inflammatory basis of hypertension.

Hypertension is a major health problem with great consequences for public health. Despite its role as the primary cause of significant morbidity and mortality associated with cardiovascular disease, the pathogenesis of essential hypertension remains largely unknown. The central nervous system (CNS) in general, and the hypothalamus in particular, are intricately involved in the development and maintenance of hypertension. Over the last several decades, the understanding of the brain's role in the development of hypertension has dramatically increased. This brief review is to summarize the neural mechanisms of hypertension with a focus on neuroendocrine and neurotransmitter involvement, highlighting recent findings that suggest that hypothalamic inflammation disrupts key signalling pathways to affect the central control of blood pressure, and therefore suggesting future development of interventional strategies that exploit recent findings pertaining to the hypothalamic control of blood pressure as well as the inflammatory-sympathetic mechanisms involved in hypertension.