Abstract
Glucose is a major fuel for the central nervous system and hypoglycemia is a significant homeostatic stressor, which elicits counterregulatory reactions. Hypothalamic metabolic- and stress-related neurons initiate these actions, however recruitment of glia in control such adaptive circuit remain unknown. Groups of fed- and fasted-, vehicle-injected, and fasted + insulin-injected male mice were compared in this study. Bolus insulin administration to fasted mice resulted in hypoglycemia, which increased hypothalamo-pituitary-adrenal (HPA) axis- and sympathetic activity, increased transcription of neuropeptide Y (Npy) and agouti-related peptide (Agrp) in the hypothalamic arcuate nucleus and activated IBA1+ microglia in the hypothalamus. Activated microglia were found in close apposition to hypoglycemia-responsive NPY neurons. Inhibition of microglia by minocycline increased counterregulatory sympathetic response to hypoglycemia. Fractalkine-CX3CR1 signaling plays a role in control of microglia during hypoglycemia, because density and solidity of IBA1-ir profiles was attenuated in fasted, insulin-treated, CX3CR1 KO mice, which was parallel with exaggerated neuropeptide responses and higher blood glucose levels following insulin administration. Hypoglycemia increased Il-1b expression in the arcuate nucleus, while IL-1a/b knockout mice display improved glycemic control to insulin administration. In conclusion, activated microglia in the arcuate nucleus interferes with central counterregulatory responses to hypoglycemia. These results underscore involvement of microglia in hypothalamic regulation of glucose homeostasis.
Highlights
Metabolic- and stress-related circuits are intimately connected with immune regulation
As a strong homeostatic stressor, hypoglycemia resulted in activation of HPA axis compared to fed [F [2, 6] = 67.93, p < 0.0001; Bonferroni’s post hoc test, t(6) = 10.71, p < 0.001] and fasted [F [2, 6] = 67.93, p < 0.0001; Bonferroni’s post hoc test, t(6) = 8.3, p < 0.001] state as indicated by elevated corticosterone concentration (Fig. 1C)
We show that insulin-induced hypoglycemia selectively activates microglia in the hypothalamic arcuate nucleus and this microglial activation likely attenuates full expression of counterregulatory responses to hypoglycemia
Summary
Metabolic- and stress-related circuits are intimately connected with immune regulation. Microglial cells are local representatives of the innate immune system in the CNS, which might be recruited in physiological responses to homeostatic challenges. Microglia continuously screen tissue microenvironment via highly motile fine branches and become rapidly activated in response to subtle changes in synaptic activity or danger (damage)and pathogen-associated molecular patterns (DAMPs and PAMPs). Increasing evidence support the involvement of glial elements in regulation, shaping and modulation adaptive physiological responses. Increasing evidence support the involvement of glial elements in regulation, shaping and modulation adaptive physiological responses7 Along these lines, the aim of the present study was to investigate changes of hypothalamic microglia in response to a strong homeostatic/metabolic challenge, hypoglycemia and to reveal the role of microglia in control of counterregulatory responses
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