Viral Infections and Interferons in the Development of Obesity

Abstract

Obesity is now a prevalent disease worldwide and has a multi-factorial etiology. Several viruses or virus-like agents including members of adenoviridae, herpesviridae, slow virus (prion), and hepatitides, have been associated with obesity; meanwhile obese patients are shown to be more susceptible to viral infections such as during influenza and dengue epidemics. We examined the co-factorial role of viral infections, particularly of the persistent cases, in synergy with high-fat diet in induction of obesity. Antiviral interferons (IFNs), as key immune regulators against viral infections and in autoimmunity, emerge to be a pivotal player in the regulation of adipogenesis. In this review, we examine the recent evidence indicating that gut microbiota uphold intrinsic IFN signaling, which is extensively involved in the regulation of lipid metabolism. However, the prolonged IFN responses during persistent viral infections and obesogenesis comprise reciprocal causality between virus susceptibility and obesity. Furthermore, some IFN subtypes have shown therapeutic potency in their anti-inflammation and anti-obesity activity.

Keywords: interferon; lipid metabolism; obesity; persistent viral infection.

Figure 1

Intrinsic interferon (IFN) response to microbiota tonic induction may suppress obesity in addition to its role in potentiating rapid antiviral response. In homeostatic situation, gut epithelia and the underlying leukocytes (mainly macrophages and dendritic cells, for example) sense natural shedding of microbial molecules from microbiota (particularly virobiota) and sustain an intrinsic expression of innate immune IFNs, particularly including IFN-β and probably IFN-λ. Acting through a non-canonical AKT-mTOR pathway, intrinsic IFNs signal IL-10/TGF production and contribute to maintain an anti-inflammatory microenvironment, which attenuates meta-inflammation and adipogenesis related to visceral obesity. The anti-obesity effect of transfecting IFN-β was recently demonstrated in addition to its role in potentiating rapid antiviral response via IFN autocrine loop of regulation. Abbreviations: AKT-mTOR, protein kinase B and mammalian target of rapamycin pathway; CREB, cAMP response element binding protein; IFN, interferon; IFNAR, type I IFN receptor; IFNLR, type III IFN receptor; IRF, IFN regulatory factor; IL-10, interleukin 10; PAMP, pathogenic associated molecular pattern; TGF, transforming growth factor; and TLR, Toll-like receptor.

Figure 2

Antiviral IFN stimulation and the effect on energy and lipid metabolism. Counteracting viral infections, which seize the cell energy and lipid metabolism for viral production but enhance fatty acid (FA) and cholesterol synthesis, effective IFN response leads to an antiviral state through an IFN autocrine or paracrine regulatory loop. The induction of antiviral state is accompanied by a general arrest of protein and lipid metabolism. The IFN suppression of lipid metabolism is multifaceted such as directly repressing the synthesis of FA and cholesterol, and regulating via the upstream regulators of AMPK and mTOR complex. In addition, IFNs have been also implicated in the regulation of glycolysis, TCA cycle, and cholesterol transport to facilitate cell antiviral response. Taking together, the effective IFN response, especially that during acute phases of antiviral responses, is unlikely to induce obesity and meta-inflammation underlying obesity; however, the prolonged IFN responses during chronic viral infections might be an adipogenic drive in an opposite way (Figure 3). Abbreviations: acetyl-CoA, acetyl coenzyme A; Akt/PI3K/mTOR, phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway; AMPK, 5-adenosine monophosphate-activated protein kinase; FA, fatty acid; FAO, fatty acid oxidation; IFN-I, type I interferon; 25HC, 25-hydroxycholesterol; ROS, reactive oxygen species; SREBP, sterol regulatory binding protein; TCA cycle, tricarboxylic acid cycle. Adapted from [80,81] with a permission.

Figure 3

A reciprocal causality of obesity and chronic viral infections. High-fat diet and viral infection (particularly chronic viral infections) may independently (or synergistically in most time) induce dysbiosis of gut microbiota leading to gut inflammation and leaking, which at least partly results from prolonged IFN production upon chronic viral infection and underlies systemic inflammation of obesity. In turn, through the production of long-chain fatty acid (LFA) and leptin by expanding adipocytes, obesity is accompanied with meta-inflammation (enhanced by LFA) and susceptibility to viral infections (through suppression of IFN antiviral signaling by leptin induction of SOCS3 signaling). Abbreviations: NF-κB, nuclear factor-kappa B; P-STAT, phosphorylated signal transducer and activator of transcription; RIG-I, retinoic acid-inducible gene I; SOCS3, suppressor of cytokine signaling 3; TNF, tumor necrosis factor; and that in the legend of Figure 1.