The innate immune kinase TBK1, or TANK-binding kinase 1, plays a crucial role in responding to signals derived from microbes, initiating defense mechanisms against viral and bacterial pathogens. More recent research has also implicated TBK1 in metabolic processes and the development of tumors. The kinase mTOR, or mechanistic target of rapamycin, acts as a central integrator of various environmental signals, controlling fundamental cellular processes such as growth, metabolism, and survival.

Our previous work in cellular models demonstrated that TBK1 phosphorylates mTOR at a specific site, serine 2159 (S2159), leading to increased catalytic activity and signaling of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). In this study, we investigated the role of TBK1-mTOR signaling in the control of glucose metabolism in living organisms. We found that mice with diet-induced obesity, or DIO, but not lean mice that carried a whole-body knock-in allele resulting in an “TBK1-resistant” Mtor, specifically the Mtor S2159A allele (MtorA/A), displayed worsened hyperglycemia, which is high blood sugar, and systemic insulin resistance.

Importantly, these changes occurred without any alteration in their overall energy balance. Mechanistically, the Mtor S2159A knock-in in DIO mice led to a reduction in both mTORC1 and mTORC2 signaling in response to insulin and agonists of the innate immune system. These mice also showed reduced expression of anti-inflammatory genes in their adipose tissue, and a blunted ability of macrophages to polarize into the anti-inflammatory M2 phenotype.

These phenotypes were similar to those observed in mice with tissue-specific inactivation of either TBK1 or the mTOR complexes themselves. Furthermore, tissues from DIO mice exhibited elevated TBK1 activity and increased phosphorylation of mTOR at S2159 compared to tissues from lean mice. TBK1/IKKε-IN-5 Based on these findings, we propose a model in which the signals associated with obesity lead to increased TBK1 activity and subsequent phosphorylation of mTOR.

This phosphorylation event enhances mTORC1 and mTORC2 signaling in parallel to the insulin signaling pathway, thereby counteracting insulin resistance and improving the control of blood glucose levels during diet-induced obesity.