Setting the Inflammatory Tone
Our studies and others suggest that SirT1 is a key participant in the inflammation that occurs in obesity through its actions in adipocytes and macrophages. Interestingly, unlike other proposed players in obesity-associated inflammation, SirT1 does not appear to act by providing novel ligands to stimulate immunologic receptors. Nor does it act as a sensor for an inflammatory ligand, a mediator to transduce inflammatory signals, or as a target for those mediators. Rather, SirT1 appears to act as a network regulator, which modifies the sensitivity of inflammatory circuits and thereby determines the outcome of circuit activation (Fig. 3). Network regulators like SirT1 may theoretically act at any point in the four-part model of inflammation. Given that microbial (e.g., LPS) and endogenous (i.e., fatty acid) inducers are ubiquitous, inflammation can thus result from increased sensitivity of sensors to inducers, increased elaboration of mediators in response to sensor activation, or increased response of effectors to mediators. This alteration of the circuit may be both quantitative and qualitative, changing not only the degree of inflammation (e.g., amount of cytokine produced), but also the type (e.g., ratio of “type 1” to “type 2” cytokines). Such a model could explain the ontology of metabolic inflammation.