SirT1 acts on many substrates, including histones, FoxO, NFκB and p53. How acetylation alters the function of these proteins remains incompletely understood. In the case of NFκB, acetylation appears to be an important determinant of transcriptional activity once evoked.39 Deacetylation of FoxO may contribute to both its likelihood of translocating to the nucleus, and the gene targets that it chooses to activate.40 At various sites, the (de)acetylation of histones may either open/close chromatin directly, or simply make it a more attractive target for transcriptional machinery. Thus, deacetylation of targets by SirT1 is, in general, a mechanism by which cells alter transcriptional activity both quantitatively and qualitatively in response to changing nutrient status.33
Phenomena such as LPS tolerance, wherein the response to LPS is qualitatively and quantitatively altered by prior exposure, have clearly demonstrated that inflammatory circuits can be modified depending on the context in which they occur.41-43 While such modulation could theoretically occur through many means—ligand scavenging, receptor antagonism or desensitization, inhibitors of transcriptional activity—epigenetic modification of target genes may be a common methodology. Such mechanisms may change the threshold for activation, the system gain, or the transcriptional targets in order that the same amount of inducer provoke a different degree or type of inflammatory response.
We believe the circuit-modifying role of SirT1 is further evidence that the immune system and nutrition have a hard-wired and adaptive association in physiology, as well as pathophysiology. As discussed, suppression of inflammation in the undernourished state may be critical to resource allocation. It remains unclear, however, whether the converse should also be true: whether inflammation should be disinhibited in an overnourished state. In this vein, one possibility we find interesting is that “parainflammation”4 might play an important physiological role in regulating metabolism in response to environmental stressors. In this formulation, the immune system is viewed more as a “general manager” of tissue homeostasis as opposed to specialized system for pathogen disposal. Such speculations are supported by accumulating observations that animals with altered immune function spontaneously develop disordered food intake, metabolic rate, substrate utilization and adipose tissue depot size.32,44-46 We anticipate many surprises in this vigorous field over the next several decades, ultimately leading to an integrative perspective on the link between metabolism and immunology, as well as new therapeutic avenues.

Materials and Methods

Male C57BL6 mice were fed high-fat diet (60% kcal from fat, D12492, Research Diets) or regular chow (2018s, Harlan Teklad) for 16 weeks. Macrophages were harvested by peritoneal lavage, RNA was extracted using the RNeasy Kit (Qiagen), reverse transcribed and gDNA removed with the QuantiTect Kit (Qiagen), and transcript abundance assessed by real-time PCR on a 7500 Fast Real-Time PCR System (Applied Biosystems) and analyzed by ΔΔCt method with SirT1 primer sequences F: 5′-CACAAATACTGCCAAGATGTGAAT-3′, R: 5′-TCCAAAATATTACACTCTCCCCAGTA-3′.

Acknowledgments

The authors would like to thank Dr Gerald Shulman and members of his laboratory for formative discussions and the University of Iowa Department of Neurology for research support.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

References

1. Ford ES, Mokdad AH. Epidemiology of obesity in the Western Hemisphere. J Clin Endocrinol Metab. 2008;93(Suppl 1):S1–8. doi: 10.1210/jc.2008-1356. [PubMed] [Cross Ref]