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 integrate innate immune and metabolic responses and protect against obesity-linked type II diabetes- revealing potential new therapeutic opportunities.
This project will define how an innate immune kinase (TBK1) signals through a metabolic kinase (mTOR) to integrate innate immune function with metabolism to protect against insulin resistance and impaired glycemic control during diet-induced obesity by studying genetically modified mice. It will thus advance our understanding of the pathogenesis of obesity-linked type II diabetes and may reveal therapeutic opportunities.
