Fig. 4.

Schematic representation of potential intercellular interaction in hypothalamic inflammation associated with metabolic diseases. Hypercaloric environments, such as increased FAs and glucose or immunological factors, induce glial activation and hypothalamic inflammation. Higher circulating FAs and glucose are transported into the hypothalamus through the permeable blood capillaries. Tanycytes, a specialized ependymal cell type located in the lateral walls and surface of the third ventricle, allow the dynamic passage of nutrients, including FAs and glucose, from the circulation to the hypothalamus. Tanycytes express VEGF, which targets microvessel loops and increases the permeability of the vessels and may also contribute to chronic inflammation. In metabolic diseases like obesity and diabetes, increased level of FAs activates both microglia and astrocytes, primarily by binding to TLRs in microglia. Similarly, FAs cause accumulation of lipid droplets in astrocytes, leading to inflammatory activation of astrocytes and releasing proinflammatory mediators, including chemokine MCP-1, which may further activate microglia by molecular interaction, causing sustainable and enhanced inflammation. The lipid-laden reactive astrocytes can also interact with the microglia through the membrane-bound costimulatory receptor/ligand, such as 4-1BB/4-1BBL, enhancing the inflammatory activity of both microglia and astrocytes. Neurons release CX3CL1 following hypercaloric insult and are thought to bind with a chemokine receptor CX3CR1 expressed in the microglia, leading to inflammatory activation of the microglia. Solid purple arrows, reported cellular interaction; dotted purple arrows, possible interaction; solid red arrows, upregulated; solid blue arrows, downregulated. FAs fatty acids, TLR toll-like receptor, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor, MCP-1 monocyte chemoattractant protein 1, CCR2 C–C chemokine receptor type 2, CX3CL1 chemokine (C-X-C motif) ligand 1, CXCL1R CX3C chemokine receptor 1