# Profiling the role of conventional type 1 dendritic cells during obesity-associated inflammation

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Obesity has become a global health epidemic, affecting nearly 30% of the world’s population. Obesity is
associated with the development chronic low-grade inflammation which can lead to insulin resistance, implicating
a role for obesity-associated inflammation in the induction of type II diabetes mellitus (T2DM). However, the
underlying causes of adipose tissue inflammation during obesity remain poorly understood. Accumulation and
activation of tissue-resident macrophages has been shown to contribute to inflammation and insulin resistance
in mice, a process regulated by type 1 immune cell such as CD8+ and CD4+ TH1 cells, natural killer (NK) cells,
and type 1 innate lymphoid cells (ILC1). Our lab has shown previously that ILC1-derived interferon gamma (IFN-
γ) drives proinflammatory macrophage accumulation and contributes to obesity-associated insulin resistance in
response to interleukin-12 (IL-12). Previous findings have implicated IL-12 signaling in obesity-associated
inflammation and subsequent metabolic dysfunction, but the cellular sources of IL-12 during obesity remain
unknown. Conventional type 1 dendritic cells (cDC1) are potent activators of type 1 immune responses and
produce IL-12 in response to pathogen challenge. However, whether cDC1 produce IL-12 within the adipose
tissue during obesity is unknown. Furthermore, while obesity-associated increases in dendritic cell infiltration
have been reported, the mechanisms that govern dendritic cell recruitment into the WAT are poorly understood.
As such, the precise function of cDC1 in potentiating adipose tissue inflammation and insulin resistance during
obesity remains to be elucidated.
My preliminary data supports the central hypothesis that cDC1 are recruited into the adipose tissue by NK cell-
derived XCL1, whereupon they initiate proinflammatory cytokine responses via IL-12 production to contribute to
obesity-associated inflammation and insulin resistance. My rationale is that cDC1 accumulate in both human
and mouse adipose tissue during obesity and that they are the major producers of IL-12 in mouse models of
diet-induced obesity. Furthermore, we find that the XCL1-XCR1 signaling axis is enriched in obese patients and
that genetic depletion of NK cells in mice significantly reduces cDC1 accumulation within the adipose tissue. I
propose to test my central hypothesis using the following aims: Aim 1: determine the role of cDC1 during diet-
induced obesity (DIO) and Aim 2: elucidate the mechanisms that drive cDC1 accumulation into the adipose
tissue during DIO. This approach is significant, as completion of the proposed research will provide novel
insights into how the innate immune system contributes to the initiation and potentiation of obesity-associated
inflammation and insulin resistance, opening the door for the development of novel therapeutic targets aimed at
preventing the development of insulin resistance and onset of T2DM.

## Key facts

- **NIH application ID:** 10463474
- **Project number:** 1F31DK130585-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Andrew Douglas Hildreth
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463474

## Citation

> US National Institutes of Health, RePORTER application 10463474, Profiling the role of conventional type 1 dendritic cells during obesity-associated inflammation (1F31DK130585-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10463474. Licensed CC0.

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