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Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto-N-fucopentaose III (LNFPIII), a Lewis(X)-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-α, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases.

The formation of an atherosclerotic lesion is mediated by lipid-laden macrophages (foam cells), which also establish chronic inflammation associated with lesion progression. The peroxisome proliferator-activated receptor (PPAR) gamma promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARdelta controls the inflammatory status of the macrophage. Deletion of PPARdelta from foam cells increased the availability of inflammatory suppressors, which in turn reduced atherosclerotic lesion area by more than 50%. We propose an unconventional ligand-dependent transcriptional pathway in which PPARdelta controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARdelta and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.

Background/Objective: Nicardipine is a calcium channel blocker that has been widely used to control blood pressure in severe hypertension following events such as ischemic stroke, traumatic brain injury, and intracerebral hemorrhage. However, accumulating evidence suggests that inflammatory processes in the central nervous system that are mediated by microglial activation play important roles in neurodegeneration, and the effect of nicardipine on microglial activation remains unresolved. Methodology/Principal Findings: In the present study, using murine BV-2 microglia, we demonstrated that nicardipine significantly inhibits microglia-related neuroinflammatory responses. Treatment with nicardipine inhibited microglial cell migration. Nicardipine also significantly inhibited LPS plus IFN-γ-induced release of nitric oxide (NO), and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, nicardipine also inhibited microglial activation by peptidoglycan, the major component of the Gram-positive bacterium cell wall. Notably, nicardipine also showed significant anti-neuroinflammatory effects on microglial activation in mice in vivo. Conclusion/Significance: The present study is the first to report a novel inhibitory role of nicardipine on neuroinflammation and provides a new candidate agent for the development of therapies for inflammation-related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

In recent years white adipose tissue inflammation has been recognized to be associated with obesity. Adipocytes and adipose tissue associated macrophages (ATMs) secrete bioactive molecules, including adipokines, chemokines/cytokines and free fatty acids that modulate the development of low-grade inflammation and insulin resistance responsible for obesity-related metabolic and cardiovascular diseases. Nuclear receptors, notably peroxisome-proliferator-activated receptors, are sensors of dietary lipids and control transcriptional programs of key metabolic and inflammatory pathways in adipocytes and macrophages. This review focuses on mechanisms by which nuclear receptors maintain white adipose tissue homeostasis. The identification of ATMs as active players in the initiation of chronic inflammation and the links between inflammatory signaling and metabolic dysfunction will be presented, followed by discussion of recent evidence for nuclear receptors in ATM function, with an emphasis on the paracrine interaction between adipocytes and ATMs. [ABSTRACT FROM AUTHOR]