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Review
. 2021 Mar 26;22(7):3456.
doi: 10.3390/ijms22073456.

The Inflammatory Profile of Obesity and the Role on Pulmonary Bacterial and Viral Infections

Franziska Hornung  1 , Julia Rogal  2   3 , Peter Loskill  2   3 , Bettina Löffler  1 , Stefanie Deinhardt-Emmer  1   4
Affiliations
Review

The Inflammatory Profile of Obesity and the Role on Pulmonary Bacterial and Viral Infections

Franziska Hornung et al. Int J Mol Sci. .

Abstract

Obesity is a globally increasing health problem, entailing diverse comorbidities such as infectious diseases. An obese weight status has marked effects on lung function that can be attributed to mechanical dysfunctions. Moreover, the alterations of adipocyte-derived signal mediators strongly influence the regulation of inflammation, resulting in chronic low-grade inflammation. Our review summarizes the known effects regarding pulmonary bacterial and viral infections. For this, we discuss model systems that allow mechanistic investigation of the interplay between obesity and lung infections. Overall, obesity gives rise to a higher susceptibility to infectious pathogens, but the pathogenetic process is not clearly defined. Whereas, viral infections often show a more severe course in obese patients, the same patients seem to have a survival benefit during bacterial infections. In particular, we summarize the main mechanical impairments in the pulmonary tract caused by obesity. Moreover, we outline the main secretory changes within the expanded adipose tissue mass, resulting in chronic low-grade inflammation. Finally, we connect these altered host factors to the influence of obesity on the development of lung infection by summarizing observations from clinical and experimental data.

Keywords: adipocytokines; bacteria; lung infection; obesity; obesity paradox; viruses.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
The remodeling process in adipose tissue during weight gain. White adipose tissue is primarily composed of adipocytes, macrophages and blood vessels. To cope with an elevated amount of triacylglycerols (TG) during weight gain, adipocytes increase in size (hyperplasia) and number (hypertrophy). This can further result in the apoptosis of adipocytes, chemotactic regulations, hypoxia and free fatty acids. All four mechanisms are discussed to foster the heightened migration of macrophages into the adipose tissue. Moreover, the secretions of different adipocytokines, produced in adipocytes, macrophages or in both cell type, are influenced. In general, anti-inflammatory secretory products are downregulated, whereas the secretion of pro-inflammatory adipocytokines is elevated. These developments provide a low-grad pro-inflammatory environment, which arises from the increased and remodeled adipose tissue in obese subjects.
Figure 2
Figure 2
Overview of the leptin signaling pathway. The long isoform of the leptin receptor (ObRb) possesses the whole intracellular domain, with the conserved tyrosine residues (Y985, Y1077, Y118). The central function of leptin in the hypothalamus is regulated via the activation of anorexigenic neurons and orexigenic Neuropeptide Y (NPY)/Agouti-related Protein (AgRP) neurons. The most prominent downstream signaling component of the leptin receptor is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. After binding of leptin, subsequent dimerization of the receptor and the following activation of JAK2 occurs, followed by the recruitment of the Src homology 2 (SH2) domain of STAT3 to the conserved phosphorylated tyrosine Y705 residue. Hereinafter, STAT3 itself is phosphorylated by the JAKs at position Y705, dimerizes, and translocates into the nucleus. At this point, it serves as a regulator of the expression of different STAT3 responsive genes. One prominent downstream gene is the suppressor of cytokine signaling 3 (SOCS3), which itself acts as a potent negative regulator of the leptin signaling, by binding of Y985 domain and following inhibition of JAK2. Protein tyrosine phosphatase 1 B (PTP1B), produced in the endoplasmic reticulum (ER), is further able to inhibit leptin signaling by dephosphorylating JAK2. Besides STAT3, STAT5 is also known to be activated and phosphorylated in vivo. Another downstream signaling branch of leptin is the Mitogen-activated protein kinase (MAPK) pathway. Here, the SH2 domain of the phosphatase SH2- containing protein tyrosine phosphatase 2 (SHP2) binds to pY985, becomes phosphorylated by JAKs, which finally activates MAPK extracellular signal-related kinase (ERK1/2) via recruitment of growth factor receptor-bound protein 2 (Grb2). The phosphatidylinositol 3 kinase (PI3K) signaling pathway is activated by leptin. IRS 2 (insulin receptor substrate 2) binds to ObRb through the SH2B1 domain, able to interact and upregulate JAK2. Those IRS proteins are then capable of binding and activating PI3K yielding the subsequent accumulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) and activation of 3-phosphoinositide- dependent protein kinase (PDK1) and Akt. The latter inhibits forkhead box O1 (Foxo1), the mediator of the previously mentioned function of leptin in the hypothalamus. Another component downstream of Akt is the Ser/Thr kinase mTOR (mammalian target of rapamycin), another sensor of the availability of nutrients and stimulator of cell growth, protein biosynthesis, and proliferation. The AMPK (adenosine monophosphate-activated protein kinase) pathway is stimulated by leptin as well, but the outcome differs between the tissues. While activated in hepatocytes and muscle, AMPK is inhibited in the hypothalamus, resulting in inhibition of food intake.
Figure 3
Figure 3
Adipose tissue in vitro models (A) Membrane mature adipocyte aggregate cultures (MAACs) enabling long-term culture of buoyant primary adipocytes. Reproduced and slightly modified from [160] (CC BY 4.0); (B) Microanalytical fluidic system for the monitoring of glycerol secretion from adipocytes at a 3.5 s temporal resolution. Reproduced from Ref. [164] with permission from The Royal Society of Chemistry; (C) Organ-on-chip for studying adipocyte-immune interaction with integrated biosensors for cytokine measurement. Reproduced from Ref. [165] with permission from The Royal Society of Chemistry; (D) Adipose-on-chip integrating human mature adipocytes into a micro-physiological environment featuring vasculature-like perfusion. Reproduced from reference [167] (CC BY 4.0)”.
Figure 4
Figure 4
The impact of obesity and bacterial and viral infections. Overview of observations gained from clinical studies and experimental approaches regarding bacterial and viral infections in obese subjects with corresponding sources.
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