# Metabolic Regulation by Glial Inflammatory Signaling

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $594,805

## Abstract

Project Summary
Obesity is a significant public health concern worldwide, and the incomplete understanding of its pathogenesis
has limited the development of effective treatments. Overnutrition triggers immune cell activation in peripheral
tissues and the brain, suggesting that strategies to target the inflammatory response have theoretical
therapeutic potential. However, these approaches remain largely untested. We recently demonstrated that
mice lacking IKKβ in brain glia (astrocytes and microglia) show reduced susceptibility to diet-induced obesity
(DIO) and hyperphagia, but with different kinetics. Microglial activation occurs earlier and is required for DIO
susceptibility from the onset of HFD feeding whereas astrocyte protection from DIO only occurs after weeks of
HFD exposure. Consistent with the known role of microglia to induce reactive astrocytosis in CNS inflammatory
diseases, these data suggest a cascade of inflammatory activation beginning with microglia that subsequently
triggers astrocytes to promote DIO.
Another stark difference between the mouse models is a paradoxical impairment of glucose tolerance in the
lean microglial IKKβ knockout, suggesting dissociation between the regulation of energy balance and glucose
homeostasis by microglia. However, the molecular mediators responsible for this phenotype remain unknown.
We have now developed a diet-independent inducible model of microglial activation using the Designer
Receptor Activated by Designer Drugs (DREADD) approach. Microglia expressing the Gq-coupled DREADD
receptor hM3D are rapidly activated by CNO treatment with marked upregulation of TNFa expression.
Nevertheless, the CNO treatment causes an immediate improvement in glucose tolerance even in HFD-fed
mice. Unexpectedly, this effect can be blocked using icv pretreatment with either a specific TNF receptor
antagonist or a melanocortin 3/4 receptor antagonist. While TNF signaling can disrupt leptin sensitivity in
hypothalamic neurons, it also increases POMC neuron firing, promotes synaptic plasticity and activates the
melanocortin pathway. Therefore, we hypothesize that HFD feeding acts through microglial TLR4 to
triggers DIO susceptibility but improve glucose tolerance through the melanocortin pathway. To
investigate these premises further, in Aim 1 we will determine whether astrocyte activation is dependent on
microglial inflammatory signaling and required for microglia-induced DIO. Aim2 will determine whether
microglial TNF and melanocortin signaling are required for the improved glucose tolerance induced by
microglial activation. Finally, Aim 3 investigates the peripheral mechanisms of improved glucose tolerance and
includes a transcriptomic screen for additional microglial mediators of glucose homeostasis regulation.
Together, these studies will help identify the cellular and molecular components of microglial activation that
mediate its impact on obesity and diabetes pathogenesis.

## Key facts

- **NIH application ID:** 9968317
- **Project number:** 5R01DK119754-03
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** JOSHUA P THALER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $594,805
- **Award type:** 5
- **Project period:** 2018-09-12 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968317

## Citation

> US National Institutes of Health, RePORTER application 9968317, Metabolic Regulation by Glial Inflammatory Signaling (5R01DK119754-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9968317. Licensed CC0.

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