# Integration of innate immune function and metabolism by the TBK1-mTOR axis

> **NIH NIH R56** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $156,000

## Abstract

Project Summary
 Obesity-linked diabetes represents a complex metabolic disorder with increasing prevalence worldwide.
The conserved kinase mTOR (mechanistic target of rapamycin), which comprises the catalytic core of two
functionally distinct multiprotein complexes (raptor-containing mTORC1 and rictor-containing mTORC2),
promotes glucose and lipid homeostasis in vivo. mTOR functions as a conserved nutrient sensor that integrates
a diverse array of local and systemic signals to control cell metabolism and cell growth. Aberrant mTOR function
contributes to type II diabetes and a variety of immune disorders (among other diseases). Despite the physiologic
importance of mTOR, major gaps exist in our basic understanding of mTOR regulation and function and how
mTOR cooperates with other signaling systems to control integrative physiology. Recent work from our lab
(Bodur et al. EMBO J 2018) provides the scientific premise for this proposal, demonstrating that the innate
immune kinase TBK1 phosphorylates mTOR (on S2159) directly to activate mTORC1 and mTORC2 signaling.
Moreover, the ability of TBK1 to promote production of IFNb, a type I interferon that initiates first-line host defense
against infectious microbes, requires mTOR S2159 phosphorylation and mTORC1 activity. This work directly
linked two signaling systems not previously known to functionally interact. As prior work reported that adipocyte-
specific Tbk1 knockout (KO) causes systemic insulin resistance in mice (as does adipocyte-specific KO of Mtor,
Raptor (mTORC1), or Rictor (mTORC2)), we decided to investigate a potential role for TBK1-mTOR signaling in
metabolic control by generating a “TBK1 resistant” mTOR knock-in mouse allele bearing non-phosphorylatable
Ala at S2159 (MtorA). Our preliminary results indicate that diet-induced obese (DIO) MtorA/A mice exhibit insulin
resistance, hyperinsulinemia, and hyperglycemia despite unchanged body weight and adiposity relative to DIO
controls. Our central hypothesis posits that TBK1-mTOR signaling protects against insulin resistance and
hyperglycemia during obesity. Specifically, we hypothesize that that TBK1-mTOR signaling in adipose tissue
promotes nutrient storage in adipocytes and protects from ectopic lipid deposition and insulin resistance during
obesity. We thus further postulate that TBK1-mTORC1 signaling in adipocytes and macrophages mediates anti-
inflammatory responses that promote systemic insulin sensitivity and glycemic control during DIO. To define
roles for adipocyte and macrophage-specific TBK1-mTOR signaling in metabolic control, we will determine the
mechanisms by which adipocyte TBK1-mTOR signaling promotes glucose homeostasis during obesity (Aim 1)
and define the role of TBK1-mTOR signaling in macrophages for control of innate immune function and glycemic
control during obesity (Aim 2). In addition to defining physiologic roles for TBK1-mTOR signaling in vivo, this
project will enhance our understanding of mechanisms that integ...

## Key facts

- **NIH application ID:** 10161014
- **Project number:** 1R56DK126328-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Diane C. Fingar
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,000
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10161014

## Citation

> US National Institutes of Health, RePORTER application 10161014, Integration of innate immune function and metabolism by the TBK1-mTOR axis (1R56DK126328-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10161014. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*