Figure 3.

Physical activity alters circulating monocyte features and obese adipose tissue macrophage distinction. Obese state: The excess nutrients-caused adipocyte hypertrophy and cell death induce the micro hypoxia in AT. ① Although MФs accumulation is increased, constantly elevated levels of circulating non-esterified fatty acid reveal an inefficient function of MФs to maintain the AT homeostasis. These complex interactions of the immune system and adipocyte cause the release of inflammatory cytokines into the blood. Both circulating cytokines and the fatty-acids provide a chemoattractive environment. ② The increased CCL2 release and hypoxia result ③ the MON recruitment and more intensive infiltration into the AT. In AT, this inflammatory condition promotes M1 polarization leading to ④ higher number of surface receptors such as TLR4 and CCR2 which activate the influential inflammatory transcription factors, resulting in the upregulation of several inflammatory cytokine genes such as CCL and CXCL family, IFNγ, IL-6/12, and TNFα. ⑤ Circulating MONs are affected by releasing the abundant inflammatory cytokines and FFAs into the bloodstream. They might be altered toward the inflammatory types due to the increase of inflammatory receptors and, consequently, activation of inflammatory signaling cascades, causing the upregulation of more inflammatory genes. This impaired feed-forward cycle aggravates the inflammatory status in individuals with obesity. Lean state: Exercise training improves the inflammatory state through the inhibition of AT expansion (increasing energy consumption and modulation of inflammatory cascade activities (anti-inflammatory cytokine expression). It seems that the improvement of the inflammatory condition in either AT or bloodstream is induced by the reduction of the chemoattractant factors like CCL2 and FFAs. This has influenced the MФ polarization pathway toward M2. Consequently, it leads to a decrease in both the adipocyte death and the expression of inflammatory cytokine receptors on the surface of cell membrane, which resulted in the downregulation of inflammatory pathways. The circulating MONs which experience the anti-inflammatory condition obtain the features of anti-inflammatory MON subsets. Moreover, producing the strong anti-inflammatory myokines could interrupt these pathways following the exercise training, resulting in the improvement of obesity induced-inflammatory cycle.

Abbreviations: TLR4, toll-like receptor 4; CD, cluster of differentiation; fet-A, fetuin-A; CCR2, C-C chemokine receptor type 2; HIF1α, hypoxia-inducible factor 1 α; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IRF, interferon regulatory factor; STAT, signal transducer and activator of transcription; IL, interleukin; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand, TNFα, tumor necrosis factor α; IFNγ, interferon regulatory factor γ; SOCS, suppressor of cytokine signaling; CCR, C-C motif chemokine receptor; FFA, free fatty-acid; SFA, saturated fatty-acid; PGC1β, peroxisome proliferator-activated receptor co-activator 1 β; PPARγ, peroxisome proliferator-activated receptor γ; KLF4, kruppel like factor 4.