SUMMARY Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for central regulation of food intake. We interrogated whether CB1R-controlled feeding is paralleled by decreased activity of POMC neurons. Chemical promotion of CB1R activity increased feeding, and strikingly, CB1R activation also promoted neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because Designer-Receptors-Exclusively-Activated-by-Designer-Drugs (DREADD)-mediated inhibition of POMC neurons diminished, while DREADD-mediated activation of POMC neurons enhanced CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide, α-melanocyte-stimulating hormone (α-MSH), and the peptide, β-endorphin. CB1R activation selectively increased β-endorphin but not α-MSH release in the hypothalamus, and, systemic or hypothalamic administration of the opioid receptor antagonist, naloxone, blocked acute CB1R-induced feeding. These processes involved mitochondrial adaptations, which, when blocked, abolished CB1R-induced cellular responses and feeding. Together, these results unmasked a previously unsuspected role of POMC neurons in promotion of feeding by cannabinoids.

We have shown that synaptic re-organization of hypothalamic feeding circuits in response to metabolic shifts involves astrocytes, cells that can directly respond to the metabolic hormone, leptin, in vitro. It is not known whether the role of glia cells in hypothalamic synaptic adaptions is active or passive. Here we show that leptin receptors are expressed in hypothalamic astrocytes and that conditional, adult deletion of leptin receptors in astrocytes leads to altered glial morphology, decreased glial coverage and elevated synaptic inputs onto pro-opiomelanocortin (POMC)- and Agouti-related protein (AgRP)-producing neurons. Leptin-induced suppression of feeding was diminished, while rebound feeding after fasting or ghrelin administration was elevated in mice with astrocyte-specific leptin receptor deficiency. These data unmask an active role of glial cells in the initiation of hypothalamic synaptic plasticity and neuroendocrine control of feeding by leptin.

A core-shell structured Si nanoparticles@TiO2-x/C mesoporous microfiber composite has been synthesized by an electrospinning method. The core-shell composite exhibits high reversible capacity, excellent rate capability, and improved cycle performance as an anode material for Li-ion batteries. Furthermore, it shows remarkable suppression of exothermic behavior, which can prevent possible thermal runaway and safety problems of the cells. The improved electrochemical and thermal properties are ascribed to the mechanically, electrically, and thermally robust shell structure of the TiO2-x/C nanocomposite encapsulating the Si nanoparticles, which is suggested as a promising material architecture for a safe and reliable Si-based Li-ion battery of high energy density.

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Obesity, a condition characterized by increased fat content and altered secretion of adipokines, is a risk factor for postmenopausal breast cancer. Visfatin has recently been established as a novel adipokine that is highly enriched in visceral fat. Here we report that visfatin regulated proliferation of MCF-7 human breast cancer cells. Exogenous administration of recombinant visfatin increased cell proliferation and DNA synthesis rate in MCF-7 cells. Furthermore, visfatin activated G1-S phase cell cycle progression by upregulation of cyclin D1 and cdk2 expression. Visfatin also increased the expression of matrix metalloproteinases 2, matrix metalloproteinases 9, and vascular endothelial growth factor genes, suggesting that it may function in metastasis and angiogenesis of breast cancer. Taken together, these findings suggest that visfatin plays an important role in breast cancer progression.

Various pathophysiologic mechanisms leading to sickness behaviors have been proposed. For example, an inflammatory process in the hypothalamus has been implicated, but the signaling modalities that involve inflammatory mechanisms and neuronal circuit functions are ill-defined. Here, we show that toll-like receptor 2 (TLR2) activation by intracerebroventricular injection of its ligand, Pam3CSK4, triggered hypothalamic inflammation and activation of arcuate nucleus microglia, resulting in altered input organization and increased activity of proopiomelanocortin (POMC) neurons. These animals developed sickness behavior symptoms, including anorexia, hypoactivity, and hyperthermia. Antagonists of nuclear factor kappa B (NF-κB), cyclooxygenase pathway and melanocortin receptors 3/4 reversed the anorexia and body weight loss induced by TLR2 activation. These results unmask an important role of TLR2 in the development of sickness behaviors via stimulation of hypothalamic microglia to promote POMC neuronal activation in association with hypothalamic inflammation.A growing body of evidence indicates that an inflammatory process in the hypothalamus is one of the major causes of dysfunctions in energy metabolism. In particular, previous studies have focused on events of chronic inflammation, which is an important pathologic element leading to metabolic syndromes 1,2 . However, the significance of acute hypothalamic inflammation in sickness behaviors has been relatively ignored even though it is closely correlated with human diseases such as infection and cachexia 3 . Sickness responses are coordinated sets of adaptive behavioral changes including loss of appetite, hypoactivity, and hyperthermia during the course of human diseases such as cancer, acquired immune deficiency syndrome (AIDS), tuberculosis, and renal failure 4 . Although hypothalamic inflammation has been recognized as a prominent component of sickness responses 5,6 , the pathophysiologic mechanisms of sickness symptoms are poorly understood.Toll-like receptors (TLRs) are key components of the innate immune system through their role in the recognition of a variety of pathogens and inflammatory signals 7 . Recently, it has been proposed that perturbation of metabolic controls is closely associated with the function of TLRs as inflammatory modulators [8][9][10] . In the development of diet-or ageing-induced obesity, the function of TLRs in the neural cells is thought to be as important as their impact on peripheral organs 11,12 . Nevertheless, it remains unclear whether TLRs participate in the development of sickness behaviors governed by hypothalamic neural circuits. Therefore, in this study, we interrogated the role of hypothalamic TLR2 in the development of sickness behaviors caused by acute hypothalamic inflammation.We found that intracerebroventricular (icv) injection of the TLR2 ligand Pam3CSK4 led to sickness responses including anorexia, hypoactivity, and hyperthermia through stimulation of inflammatory processes in the hypothalamus. In addition, we observe...

OBJECTIVEInflammation is an important factor in the development of insulin resistance, type 2 diabetes, and fatty liver disease. As a member of the tumor necrosis factor receptor superfamily (TNFRSF9) expressed on immune cells, 4-1BB/CD137 provides a bidirectional inflammatory signal through binding to its ligand 4-1BBL. Both 4-1BB and 4-1BBL have been shown to play an important role in the pathogenesis of various inflammatory diseases.RESEARCH DESIGN AND METHODSEight-week-old male 4-1BB–deficient and wild-type (WT) mice were fed a high-fat diet (HFD) or a regular diet for 9 weeks.RESULTSWe demonstrate that 4-1BB deficiency protects against HFD-induced obesity, glucose intolerance, and fatty liver disease. The 4-1BB–deficient mice fed an HFD showed less body weight gain, adiposity, adipose infiltration of macrophages/T cells, and tissue levels of inflammatory cytokines (e.g., TNF-α, interleukin-6, and monocyte chemoattractant protein-1 [MCP-1]) compared with HFD-fed control mice. HFD-induced glucose intolerance/insulin resistance and fatty liver were also markedly attenuated in the 4-1BB–deficient mice.CONCLUSIONSThese findings suggest that 4-1BB and 4-1BBL may be useful therapeutic targets for combating obesity-induced inflammation and metabolic disorders.