# Defining the contributions of hypothalamic microglia and perineuronal nets to obesity pathogenesis

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2024 · $176,500

## Abstract

Project Summary
An emerging model of obesity pathogenesis posits a central role for the inflammatory activation of
hypothalamic microglia localized to the arcuate nucleus (ARC, a key brain area for the control of food intake
and body weight) in the pathogenesis of diet-induced obesity (DIO), a finding observed in mammalian species
ranging from rodents to humans. While microglia activation in the ARC is a known determinant of weight gain
in high fat diet (HFD)-fed mice, it paradoxically improves glucose tolerance in DIO, but the mechanisms
underlying both of these metabolic effects remain unclear. Herein, we report the novel finding that in mice, DIO
induces loss of specialized extracellular matrix (ECM) structures known as perineuronal nets (PNNs) in the
same brain area where reactive gliosis occurs. PNNs can powerfully influence the activity of neurons that they
enmesh, and in the ARC, a large proportion of AgRP and a subset of POMC neurons are among those
enmeshed by PNNs. These neurons are central regulators of energy homeostasis, and their altered function in
DIO is strongly implicated in obesity pathogenesis and glucose regulation. Importantly, ablating or silencing
microglia reduces Npy and AgRP levels and increases POMC neuron excitability, suggesting a link between
microglial activation and ARC neuronal function that promotes weight gain. Furthermore, DIO is associated
with loss of hypothalamic PNNs in proportion to the degree of microglial activation, with PNN stability
enhanced by interventions that ablate or limit the inflammatory capacity of microglia. Finally, removal of
hypothalamic PNNs experimentally causes gliosis, hyperphagia and rapid weight gain with preserved glucose
tolerance in rodents, providing strong evidence that microglia and PNNs are linked in a critical mechanism that
underlies obesity pathogenesis. Here, we investigate the inter-related hypotheses that obesity-associated
microglial activation induces loss of PNN enmeshment of ARC neurons, thereby altering AgRP and Pomc
neuron function in ways that promote excess fat accumulation but maintain glucose tolerance. Proposed
studies will first quantify the role played by microglia to regulate ARC PNN turnover. We will then 1) determine
whether the effect of DIO to induce loss of ARC PNNs depends on microglial activation, 2) identify the roles of
both microglial activation and PNN loss in obesity-associated dysfunction of AgRP and POMC neurons, and 3)
determine the bidirectional contributions linking ARC PNN loss and microglial activation to DIO susceptibility.

## Key facts

- **NIH application ID:** 11091684
- **Project number:** 1R56DK140210-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael W Schwartz
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $176,500
- **Award type:** 1
- **Project period:** 2024-08-03 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11091684

## Citation

> US National Institutes of Health, RePORTER application 11091684, Defining the contributions of hypothalamic microglia and perineuronal nets to obesity pathogenesis (1R56DK140210-01). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/11091684. Licensed CC0.

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