SUN-685 - Glucose-Induced Changes in Adhesion G-Protein Coupled Receptor 1 (Adgrl1) mRNA Expression in Neurons and Non-Neuronal Cells

The major energy substrate of the brain cells, glucose, acts as a nutrient signal in controlling energy homeostasis. A subset of hypothalamic neurons, as well as non-neuronal cells, have the ability to respond to changes in local glucose concentration. Recent studies demonstrated that adhesion G-protein coupled receptor 1 (Adgrl1) is expressed in hypothalamic glucose-sensing neurons, including feeding-regulating neurons, and binds glucose. Global or hypothalamus-specific Adgrl1 deficiency causes hyperphagia, obesity, and impaired insulin sensitivity in mice. Glucose-induced feeding suppression is attenuated in Adgrl1 deficient mice compared to wild-type mice. These findings suggest that Adgrl1 functions as a glucose receptor and participates in the regulation of energy homeostasis via hypothalamic glucose sensing. However, the precise mechanism by which hypothalamic Adgrl1 mediates glucose-induced feeding suppression is unknown. We hypothesized that Adgrl1 gene expression is regulated by local glucose concentrations in hypothalamic glucose-sensing neurons and non-neuronal cells. To test this possibility, immortalized neuronal cell lines, mHypoE-N7 and mHypoA-2/30, established from embryonic and adult mouse hypothalamus, respectively, were exposed to different concentrations of glucose (0, 2.5, 5, 10, or 15 mM) for 1, 3, 6, or 12 hours and Adgrl1 mRNA expression levels were quantified by real-time PCR. To determine whether glucose affects expression of Adgrl1 mRNA is glucose-sensing non-neuronal cells, mouse microglial SIM-A9 cells were exposed to different concentrations of glucose for 6 or 24 hours. Glucose treatment for 6 hours increased Adgrl1 mRNA levels in a concentration-dependent manner in mHypoE-N7 cells. Glucose treatment at 15 mM caused a significant change in Adgrl1 mRNA levels in a time-dependent manner in these cells. Similarly, 6-h glucose treatment at 15 mM significantly increased Adgrl1 mRNA levels, while reducing orexigenic agouti-related peptide (Agrp) mRNA levels in mHypoA-2/30 cells. A transition of glucose concentration from the maintenance 17.5 mM to 25 mM caused a significant reduction of Adgrl1 mRNA levels in SIM-A9 cells both 6 and 24 hours after exposure to high glucose. These findings support our hypothesis and suggest the possibility that glucose regulates feeding-regulating neuropeptide gene expression by modulating Adgrl1 expression. Present findings also suggest that glucose differentially regulates Adgrl1 expression in neurons and microglia. Future research should investigate how glucose-mediated alterations in Adgrl1 expression mediate the effect of glucose on the activity and function of glucose-sensing neurons and microglia and how it regulates food intake and metabolism.

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