Dongsheng Cai

Significance: The epidemic of obesity has reached an alarming level worldwide. Understanding the etiology of obesity is important for identifying a new approach of prevention or treatment. Accumulating evidence demonstrates that the central nervous system plays a critical role in animal’s energy homeostasis. Here, we show that extended synaptotagmin (E-Syt3) is expressed in the hypothalamus and contributes to diet-induced obesity development. Whole-body or proopiomelanocortin neuron-specific deletion of E-Syt3 significantly protects mice against DIO and related metabolic disorders. Mechanistically, we show that inhibition of E-Syt3 can lead to increased hypothalamic content of α-melanocyte-stimulating hormone. Thus, our current work suggests that E-Syt3 might be a relevant target for treating obesity.

Prolonged obesity is associated with cerebrovascular dysfunction; however, the underlying mechanisms remain largely unclear. In the present study, using a prolonged obesity mouse model that suffers from basilar artery (BA) abnormalities, we find that microglial transforming growth factor β-activated kinase 1 (Tak1) is over-activated in the brainstem. Both pharmacological inhibition primarily in the brainstem and genetic microglia-selective deletion of Tak1 ameliorated BA vascular dysfunction. Conversely, microglia-specific activation of Tak1 in the brainstem was sufficient to cause an impairment in BA function in chow-fed mice. Mechanistically, Tak1 activation leads to increased interleukin-18 (IL-18) production, whereas blockade of IL-18 receptor in the brain helped protect against cerebrovascular dysfunction despite prolonged obesity. Microglia-selective deletion of Tak1 also protects against ischemic stroke in prolonged obesity. Taken together, these findings provide evidence that microglial Tak1 in the brain, and particularly the brainstem, contributes to the pathogenesis of obesity-associated cerebrovascular dysfunction.

We report that mouse hypothalamic stem/progenitor cells produce multiple pancreatic, gastrointestinal and hypothalamic peptides in addition to exosomes. Through cell sorting and selection according to insulin promoter activity, we generated a subpopulation(s) of these cells which formed 3D spherical structure with combined features of hypothalamic neurospheres and pancreatic islets. Through testing streptozotocin-induced pancreatic islet disruption and fatal diabetes, we found that peripheral implantation of these spheres in mice led to remarkable improvements in general health and survival in addition to a moderate antidiabetic effect, and notably these pro-survival versus metabolic effects were dissociable to a significant extent. Mechanistically, secretion of exosomes by these spheres was essential for enhancing survival while production of insulin was important for the antidiabetic effect. In summary, hypothalamic neural stem/progenitor cells comprise subpopulations with multifaceted secretion, and their derived hypothalamic islets can be implanted peripherally to enhance general health and survival together with an antidiabetic benefit.

The microarray data generated and analysed in this Article have been uploaded to the Gene Expression Omnibus (GEO) under accession number GSE113383 . Accordingly, the ‘Data availability’ section of the Methods of the original Article has been rephrased online.

It has been proposed that the hypothalamus helps to control ageing, but the mechanisms responsible remain unclear. Here we develop several mouse models in which hypothalamic stem/progenitor cells that co-express Sox2 and Bmi1 are ablated, as we observed that ageing in mice started with a substantial loss of these hypothalamic cells. Each mouse model consistently displayed acceleration of ageing-like physiological changes or a shortened lifespan. Conversely, ageing retardation and lifespan extension were achieved in mid-aged mice that were locally implanted with healthy hypothalamic stem/progenitor cells that had been genetically engineered to survive in the ageing-related hypothalamic inflammatory microenvironment. Mechanistically, hypothalamic stem/progenitor cells contributed greatly to exosomal microRNAs (miRNAs) in the cerebrospinal fluid, and these exosomal miRNAs declined during ageing, whereas central treatment with healthy hypothalamic stem/progenitor cell-secreted exosomes led to the slowing of ageing. In conclusion, ageing speed is substantially controlled by hypothalamic stem cells, partially through the release of exosomal miRNAs.

Continuous nutritional surplus sets the stage for hypertension development. Whereas moderate dietary obesity in mice is normotensive, the homeostatic balance is disrupted concurrent with an increased risk of hypertension. However, it remains unclear how the obesity-associated prehypertensive state is converted into overt hypertension. Here, using mice with high-fat-diet (HFD)–induced moderate obesity vs control diet (CD)–fed lean mice, we comparatively studied the effects of central leptin and tumor necrosis factor-α (TNFα) as well as the involvement of the neuropeptide melanocortin pathway vs the neurotransmitter glutamate pathway. Compared with CD-fed lean mice, the pressor effect of central excess leptin and TNFα, but not melanocortin, was sensitized in HFD-fed mice. The pressor effect of central leptin in HFD-fed mice was strongly suppressed by glutamatergic inhibition but not by melanocortinergic inhibition. The pressor effect of central TNFα was substantially reversed by melanocortinergic inhibition in HFD-fed mice but barely in CD-fed mice. Regardless of diet, the hypertensive effects of central TNFα and melanocortin were both partially reversed by glutamatergic suppression. Hence, neural control of blood pressure is mediated by a signaling network between leptin, TNFα, melanocortin, and glutamate and changes in dynamics due to central excess leptin and TNFα mediate the switch from normal physiology to obesity-related hypertension.