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bioRxiv · 10.1101/2021.11.08.467521

CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding

Banerjee, J.·Dorfman, M. D.·Fasnacht, R.·Douglass, J. D.·Wyse-Jackson, A. C.·Barria, A.·Thaler, J. P.
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Abstract

ObjectiveDiet-induced obesity (DIO) is associated with hypothalamic microglial activation and dysfunction of the melanocortin pathway, but the molecular mechanisms linking the two remain unclear. Previous studies have hypothesized that microglial inflammatory signaling is linked with impaired pro-opiomelanocortin (POMC) neuron function, but this mechanism has never been directly tested in vivo. We addressed this hypothesis using the specific microglial silencing molecule, CX3CL1 (fractalkine), to determine whether reducing hypothalamic microglial activation can restore POMC/melanocortin signaling in the brain to protect against DIO. MethodsWe performed metabolic analyses in mice with targeted viral overexpression of CX3CL1 in the hypothalamus exposed to high fat diet (HFD). Electrophysiologic recording in hypothalamic slices from POMC-MAPT-GFP mice was used to determine the effects of HFD feeding and microglial silencing via minocycline or CX3CL1 on GFP-labeled POMC neurons. Finally, mice with hypothalamic overexpression of CX3CL1 received central treatment with the melanocortin receptor antagonist SHU-9119 to determine whether melanocortin signaling is required for the metabolic benefits of CX3CL1. ResultsWe found that targeted expression of both soluble and membrane-bound forms of CX3CL1 in the mediobasal hypothalamus potently reduced weight gain and increased leptin sensitivity in animals exposed to high fat diet. The protective effect of CX3CL1 rescued diet-induced changes in POMC neuron excitability and required intact melanocortin receptor signaling in vivo. ConclusionOur results provide the first evidence that HFD-induced POMC neuron dysfunction involves microglial activation. Furthermore, our study suggests that the anti-obesity action of CX3CL1 is mediated through the restoration of POMC neuron excitability and melanocortin signaling.

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Banerjee, J., Dorfman, M. D., Fasnacht, R., Douglass, J. D., Wyse-Jackson, A. C., Barria, A., Thaler, J. P.. 2021-11-10. CX3CL1 action on microglia protects from diet-induced obesity by restoring POMC neuronal excitability and melanocortin system activity impaired by high-fat diet feeding. https://doi.org/10.1101/2021.11.08.467521

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