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Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates
Martin Valdearcos1, John D Douglass2, Megan M Robblee1
1The Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
Abstract:
Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.
Insights
Dietary excess causes brain inflammation in the hypothalamus, driving obesity. Controlling this microglial inflammation prevents weight gain and reduces appetite, offering new therapeutic targets for metabolic diseases.
Area of Science:
- Neuroimmunology
- Metabolic Homeostasis
- Cellular Signaling
Background:
- Dietary excess is linked to hypothalamic inflammation, specifically involving microglia.
- The precise role of microglial inflammatory signaling in the hypothalamus and its metabolic consequences are not fully understood.
Purpose of the Study:
- To investigate how microglial inflammatory signaling in the mediobasal hypothalamus (MBH) responds to dietary excess.
- To determine the impact of microglial activation on hypothalamic control of energy homeostasis and obesity development in mice.
Main Methods:
- Pharmacological depletion of microglia.
- Selective inhibition of microglial NF-κB signaling pathway.
- Genetic manipulation of A20, a negative NF-κB regulator, in microglia.
- Assessment of microgliosis, cellular infiltration, food intake, weight gain, and energy expenditure in mice under different dietary conditions.
Main Results:
- Depleting microglia or inhibiting NF-κB signaling reduced MBH microgliosis and prevented diet-induced hyperphagia and weight gain.
- Forcing microglial activation via A20 deletion induced MBH microgliosis, reduced energy expenditure, and increased food intake and weight gain, even without dietary challenge.
- Microglial activation in the MBH orchestrates a multicellular response contributing to obesity susceptibility.
Conclusions:
- Microglial inflammatory signaling in the hypothalamus is a key mediator of the metabolic response to dietary excess.
- Targeting microglial activation presents a potential therapeutic strategy for metabolic diseases like obesity.
- Non-neuronal approaches targeting hypothalamic inflammation offer a novel avenue for treating metabolic disorders.
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