The inflammatory milieu of obesity is complex, featuring a panoply of elevated plasma and tissue cytokines, and infiltration of WAT with inflammatory cells. And while much progress has been made in identifying the inducers, sensors, mediators and effectors that participate in obesity-associated inflammation, many questions remain. One particularly enigmatic aspect of these investigations is that many of the reported inducers and sensors are present and active in physiologic states other than obesity, where they do not cause overt inflammation. Free fatty acids, for example, rise into the millimolar range during fasting, evidently without causing widespread activation of TLR4 or NLRP3. This suggests that something else—other than the simple presence or absence of a ligand for innate sensors—sets a context and contributes to the decision of whether or not to induce inflammation during obesity.

Nutrient Sensing Modulates the Inflammatory Response

The majority of studies examining the interaction between obesity and inflammation have concentrated on the pathophysiological role of the immune system in metabolism. Activation of the immune system in the setting of overnutrition is often assumed to be an accident that occurs when there is an overabundance of potential immunologic ligands such as gut-derived endotoxin, fatty acids or ceramides. However, some investigators believe that the intimate association between energy metabolism and immunity is deliberate. For example, the receptivity of inflammatory networks to activation may be regulated by nutrient availability because immune activation—particularly the pyrogenic and acute phase responses—inflicts a large energetic cost. In febrile humans, each 1°C increment in temperature raises basal metabolic rate (BMR) by 10–15%.14 As a result, during sepsis, BMR may be increased by 20–25%.15 When the bumblebee, Bombus terrestris, cannot prevent activation of the immune response under energy-limited conditions, high mortality ensues.16 Similarly, calorie restriction (CR) in mice leads to defective pathogen clearance and cytokine elaboration by peritoneal macrophages during infection, consequently reducing survival by 40%.17 Interestingly, the leptin-deficient ob/ob mouse, which lives in a state of simulated starvation, shows deficits in pathogen clearance similar to those of CR mice: an effect that can be rescued by exogenous leptin administration.18,19 Humans lacking leptin also exhibit lymphopenia and T-cell hyporesponsiveness.20 Opportunity costs are evident even at the level of individual tissues. Muscle protein wasting and the transcriptional suppression of many hepatic enzymes during sepsis provide amino acids and cellular machinery to support a dramatic increase in synthesis of acute phase proteins.21
Thus, the tight integration of metabolic and immune signaling seen in mammals may reflect an optimization process that reconciles the need for vigorous defense against pathogens with available energy supplies. For this reason, many organisms have evolved mechanisms to suppress the immune system during times of energy stress. As suggested above, soluble factors such as leptin may help communicate such signals between cells. Within cells, AMPK, mTOR and sirtuins have all been shown to participate in this communication. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) sense energy depletion and repletion, respectively, and cooperate to permit an immune response only in the presence of adequate energy reserves. AICAR, a pharmacological activator of AMPK, suppresses LPS-mediated activation of NFκB while S6K1, a downstream target of mTOR, is required for leukotriene B4, TNF-α, IL-1β and IL-6 generation.20

SirT1 Opposes Inflammation in Metabolic Tissues

Sirtuin 1 (SirT1) is a NAD+-dependent protein deacetylase that coordinates the mammalian metabolic response to calorie restriction and fasting.22-25 During times of nutrient deficit, SirT1-mediated deacetylation of PGC1-α stimulates hepatic glucose production and fatty acid oxidation,22,26 while promoting metabolic efficiency through adiponectin production in adipose tissue.27
In addition to its metabolic effects, SirT1 can suppress inflammation.28,29 Overexpression of SirT1 (with Dnajc12) decreases hepatic expression of TNF-α and IL-6 in the setting of chronic high fat feeding,30 whereas liver-specific deletion of SirT1 increases hepatic NFκB activity.26 In 3T3-L1 adipocytes, reducing SirT1 levels with RNAi reduces inhibitory deacetylation of the NFκB subunit p65, and leads to increased NFκB activity at the TNF-α, IL-6, MCP-1, KC and IL-1β promoters.31 Yoshizaki et al. speculated that downregulation of SirT1 in adipose tissue of obese mice and humans “contributes to the heightened inflammatory state of adipose tissue in obesity.”
We found that suppression of SirT1 expression in vivo causes WAT inflammation and elevation of circulating TNF-α and IL-1β, resulting in anorexia and lipolysis. As in obese animals, WAT of fat-specific SirT1 KO mice shows aberrant CD11c+ macrophage recruitment and production of proinflammatory cytokines. In contrast, inflammation is reduced in WAT of high fat diet fed SirT1 overexpressing mice. Moreover, in two distinct human cohorts, WAT SirT1 mRNA expression correlated negatively with indices of macrophage infiltration.32 In our studies, the effects of SirT1 on cytokine expression were attributable to chromatin remodeling; in the absence of SirT1 deacetylase activity, H3K9 was hyperacetylated, increasing the accessibility of inflammatory cytokine promoters to NFκB. These findings are supportive of elegant recent work demonstrating a critical role for SirT1 in maintaining silent, loci-specific facultative heterochromatin at the TNF-α and IL-1β promoters.33,34

Macrophages Sense Nutritional Status through SirT1

Much argument still exists over where obesity-associated inflammation begins. A common view is that adipocytes initiate WAT cytokine production, and that macrophages simply propagate and amplify the original insult.35 However, tissue-resident macrophages, which abound in WAT, are specialized to act as sentinels for tissue pathology and are supremely sensitive to homeostatic threats.3 Moreover, macrophages, and in particular CD11c+ cells, are the primary producers of proinflammatory cytokines during metabolic disease.36 Thus, it is important to carefully assess the role of macrophages in initiating inflammation during metabolic stress.
In fact, recent work suggests that inflammation in macrophages is similarly influenced by SirT1 expression. Although we found that macrophages are not required for adipose tissue inflammation caused by SirT1 knockdown, we also found that suppression of SirT1 in peritoneal macrophages induces TNF-α mRNA expression. Similarly, RNAi targeting of SirT1 in RAW264.7 cells enhances LPS-elicited activation of the JNK and IKK pathways and increases NFκB DNA binding and cytokine secretion.31 Deletion of SirT1 in myeloid cells causes basal inflammation, NFκB hyperacetylation, and a heightened pro-inflammatory response to high fat feeding in liver and adipose tissue.37 Finally, the anti-inflammatory effects of AMPK activation in the presence of the inducers stearate and LPS require SirT1, specifically SirT1-mediated K310 deacetylation of NFκB p65.38 Thus, like adipocytes and hepatocytes, macrophages use SirT1 to determine immune responsiveness.
Building upon these observations, we sought to determine whether macrophages in vivo could also sense whole-body nutritional status using SirT1. To address this, we fed male mice high fat diet for 16 weeks, harvested peritoneal macrophages and isolated total RNA. Analysis of SirT1 expression by qPCR revealed a ~50% reduction in the high fat fed group, supporting the notion that decreases in SirT1 may also be involved in the pathogenesis of obesity-associated inflammation in macrophages in vivo (Fig. 2). These data raise the intriguing possibility that macrophages are autonomously capable of sensing whole body nutritional status, and can use this information to influence their propensity toward inflammation. Such a role could be important in determining the appropriateness of an immune response in cases of caloric deficit, in addition to calorie surfeit, such as we have discussed above.