SUMMARY Overnutrition is associated with chronic inflammation in metabolic tissues; however, whether metabolic inflammation compromises the neural regulatory systems and therefore promotes overnutrition-associated diseases remains unexplored. Our results demonstrate that a mediator of metabolic inflammation, IKKβ/NF-κB, normally remains inactive although enriched in the hypothalamic neurons; however, overnutrition atypically activates hypothalamic IKKβ/NF-κB at least through elevated endoplasmic reticulum stress in the hypothalamus. While forced activation of hypothalamic IKKβ/NF-κB interrupts central insulin/leptin signaling and actions, site- or cell-specific suppression of IKKβ either broadly across the brain, or locally within the mediobasal hypothalamus, or specifically in hypothalamic AGRP neurons significantly protects against obesity and glucose intolerance. The involved molecular mechanisms include the control of IKKβ/NF-κB over SOCS3, a core inhibitor of insulin and leptin signaling. In conclusion, the hypothalamic IKKβ/NF-κB program is a general neural mechanism for energy imbalance underlying obesity; suppressing hypothalamic IKKβ/NF-κB represents a new strategy to combat obesity and related diseases.

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.

Hypothalamic neuropeptides play essential roles in regulating energy and body weight balance. Energy imbalance and obesity have been linked to hypothalamic signaling defects in regulating neuropeptide genes; however, it is unknown whether dysregulation of neuropeptide exocytosis could be critically involved. This study discovered that synaptotagmin-4, an atypical modulator of synaptic exocytosis, is expressed most abundantly in oxytocin neurons of the hypothalamus. Synaptotagmin-4 negatively regulates oxytocin exocytosis, and dietary obesity is associated with increased vesicle binding of synaptotagmin-4 and thus enhanced negative regulation of oxytocin release. Overexpressing synaptotagmin-4 in hypothalamic oxytocin neurons and centrally antagonizing oxytocin in mice are similarly obesogenic. Synaptotagmin-4 inhibition prevents against dietary obesity by normalizing oxytocin release and energy balance under chronic nutritional excess. In conclusion, the negative regulation of synaptotagmin-4 on oxytocin release represents a hypothalamic basis of neuropeptide exocytosis in controlling obesity and related diseases.

Obesity is important for the development of type-2 diabetes as a result of obesity-induced insulin resistance accompanied by impaired compensation of insulin secretion from pancreatic beta cells. Here, based on a randomized pilot clinical trial, we report that intranasal oxytocin administration over an 8-week period led to effective reduction of obesity and reversal of related prediabetic changes in patients. Using mouse models, we further systematically evaluated whether oxytocin and its analogs yield therapeutic effects against prediabetic or diabetic disorders regardless of obesity. Our results showed that oxytocin and two analogs including [Ser4, Ile8]-oxytocin or [Asu1,6]-oxytocin worked in mice to reverse insulin resistance and glucose intolerance prior to reduction of obesity. In parallel, using streptozotocin-induced diabetic mouse model, we found that treatment with oxytocin or its analogs reduced the magnitude of glucose intolerance through improving insulin secretion. The anti-diabetic effects of oxytocin and its analogs in these animal models can be produced similarly whether central or peripheral administration was used. In conclusion, oxytocin and its analogs have multi-level effects in improving weight control, insulin sensitivity and insulin secretion, and bear potentials for being developed as therapeutic peptides for obesity and diabetes.