SummaryAging is a result of gradual and overall functional deteriorations across the body; however, it is unknown if an individual tissue works to primarily mediate aging progress and lifespan control. Here we found that the hypothalamus is important for the development of whole-body aging in mice, and the underlying basis involves hypothalamic immunity mediated by IKKβ/NF-κB and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and lifespan extension are achieved in mice through preventing against aging-related hypothalamic or brain IKKβ/NF-κB activation. Mechanistic studies further revealed that IKKβ/NF-κB inhibits GnRH to mediate aging-related hypothalamic GnRH decline, and GnRH treatment amends aging-impaired neurogenesis and decelerates aging. In conclusion, the hypothalamus has a programmatic role in aging development via immune-neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating aging-related health problems.

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Chronic endoplasmic reticulum (ER) stress was recently revealed to affect hypothalamic neuroendocrine pathways that regulate feeding and body weight. However, it remains unexplored whether brain ER stress could use a neural route to rapidly cause the peripheral disorders that underlie the development of type 2 diabetes (T2D) and the metabolic syndrome. Using a pharmacologic model that delivered ER stress inducer thapsigargin into the brain, this study demonstrated that a short-term brain ER stress over 3 d was sufficient to induce glucose intolerance, systemic and hepatic insulin resistance, and blood pressure (BP) increase. The collection of these changes was accompanied by elevated sympathetic tone and prevented by sympathetic suppression. Molecular studies revealed that acute induction of metabolic disorders via brain ER stress was abrogated by NF-κB inhibition in the hypothalamus. Therapeutic experiments further revealed that acute inhibition of brain ER stress with tauroursodeoxycholic acid (TUDCA) partially reversed obesity-associated metabolic and blood pressure disorders. In conclusion, ER stress in the brain represents a mediator of the sympathetic disorders that underlie the development of insulin resistance syndrome and T2D. D uring the recent two decades, the epidemic of type 2 diabetes (T2D) has reached an explosive scale in the United States and many other developed countries. The risk factors for the development of T2D include a group of prognostic disorders known collectively as insulin resistance syndrome, which manifests frequently in the form of glucose intolerance, insulin resistance, dyslipidemia, and blood pressure (BP) increase in association with aging and obesity. As broadly documented in the literature (1-7), all of these disorders are characterized by the existence of stress and inflammatory molecules in the circulation and various tissues. Although it is still poorly understood how all these pathophysiological changes are etiologically connected, a variety of intracellular stresses have been proposed as primary pathogenic factors (8, 9). These advances have included the recent understanding on endoplasmic reticulum (ER) stress (10-12), a set of intracellular molecular responses when the ER fails to adapt to various physiological or pathological conditions that challenge the normal functions of ER. Under diabetes-prone environmental changes, induction of ER stress was reported to occur in insulin-secreting pancreatic β-cells (13-15) and various insulin-responsive peripheral tissues (16-18), which together cause the compromised regulation of glucose homeostasis by insulin. Most recently, chronic ER stress was revealed to occur in the hypothalamus under conditions of nutritional excess and cause hypothalamic hormonal (leptin and insulin) defects that promote feeding and weight gain (19,20). Such effects of chronic brain ER stress are predicted to incur long-term pathological changes that contribute to T2D in a manner which is secondary to weight gain and obesity (19,20).The central nervo...

The brain, in particular the hypothalamus, plays a role in regulating glucose homeostasis; however, it remains unclear if the brain is causally involved in diabetic development. Here, we identified that hypothalamic TGF-β is excessive under conditions of not only obesity but aging, which are two general etiological factors of diabetes. Pharmacological and genetic approaches consistently revealed that brain TGF-β excess caused hyperglycemia and glucose intolerance in a body weight-independent manner. Cell-specific genetic models demonstrated that astrocytes are responsible for brain TGF-β excess, and POMC neurons are crucial for the pro-diabetic effect of TGF-β excess. Mechanistically, TGF-β excess induced hypothalamic RNA stress response to accelerate IκBα mRNA decay, leading to an atypical, mRNA metabolism-driven hypothalamic NF-κB activation which links obesity as well as aging to hypothalamic inflammation. In conclusion, brain TGF-β excess and induction of RNA stress response and hypothalamic inflammation are important for the pro-diabetic effects of obesity or aging.

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