Adipokines and Bacterial Metabolites: A Pivotal Molecular Bridge Linking Obesity and Gut Microbiota Dysbiosis to Target

Abstract

Adipokines are essential mediators produced by adipose tissue and exert multiple biological functions. In particular, adiponectin, leptin, resistin, IL-6, MCP-1 and PAI-1 play specific roles in the crosstalk between adipose tissue and other organs involved in metabolic, immune and vascular health. During obesity, adipokine imbalance occurs and leads to a low-grade pro-inflammatory status, promoting insulin resistance-related diabetes and its vascular complications. A causal link between obesity and gut microbiota dysbiosis has been demonstrated. The deregulation of gut bacteria communities characterizing this dysbiosis influences the synthesis of bacterial substances including lipopolysaccharides and specific metabolites, generated via the degradation of dietary components, such as short-chain fatty acids, trimethylamine metabolized into trimethylamine-oxide in the liver and indole derivatives. Emerging evidence suggests that these bacterial metabolites modulate signaling pathways involved in adipokine production and action. This review summarizes the current knowledge about the molecular links between gut bacteria-derived metabolites and adipokine imbalance in obesity, and emphasizes their roles in key pathological mechanisms related to oxidative stress, inflammation, insulin resistance and vascular disorder. Given this interaction between adipokines and bacterial metabolites, the review highlights their relevance (i) as complementary clinical biomarkers to better explore the metabolic, inflammatory and vascular complications during obesity and gut microbiota dysbiosis, and (ii) as targets for new antioxidant, anti-inflammatory and prebiotic triple action strategies.

Keywords: adipokines; bacterial metabolites; gut microbiota dysbiosis; insulin resistance; obesity; vascular disorder.

Figure 1

Comparative signaling pathways mediated by adiponectin, leptin and resistin. Adiponectin, leptin, and resistin bind to their receptors AdipoR1/2, LepR, and CAP-1, respectively. Resistin also binds to TLR4. AdipoR1/2 recruits APPL1 and activates p38MAPK, AMPK and PI3K/Akt pathways, increasing (↑) glucose uptake and adipogenesis. Simultaneously, adiponectin decreases (↓) pro-inflammatory response and promotes vasoprotection (orange). The engagement of leptin with LepR leads to JAK2 activation, initiating STAT3 dimerization. JAK2/STAT3 induction correlates with SOCS3 production, which, in turn, mediates a negative feedback on JAK2/STAT3 signaling. Similar to AdipoR1/2, LepR can induce AMPK and PI3K/Akt pathways. In contrast to adiponectin, leptin causes a pro-inflammatory response along with oxidative stress. Moreover, leptin contributes to insulin resistance by stimulating JNK activity (green). Under resistin action, CAP-1 induces the production of cAMP by the adenylyl cyclase (AC) that activates PKA. Interconnected PKA/TLR4 signaling pathways converge to recruit NF-κB, leading to inflammation and insulin resistance (yellow).

Figure 2

Comparative signaling pathways of IL-6, PAI-1 and MCP-1. IL-6, PAI-1 and MCP-1 bind to IL-6R/sIL-6R, LRP and CCR2, respectively. Subsequently, JAK2 phosphorylates two STAT3 molecules, resulting in STAT3 dimerization, DNA binding and transcription of target genes. For instance, in the IL-6 signaling pathway, this leads to SOCS3 induction which enacts a negative feedback on JAK2/STAT3 signaling. The interaction of IL-6 with IL-6R/sIL-6R activates PI3K/Akt and MAPK pathways that induce JNK, PTP1B and SOCS3, thus promoting inflammation, oxidative stress, insulin resistance and vascular disorder (green). The PAI-1 signaling pathway contributes to insulin resistance and suppresses adipogenesis (purple). Via the MCP-1 signaling pathway, the dimerized STAT3 activates G proteins, subsequently triggering PI3K/Akt, RAS/RAF/MEK/ERK and adenylyl cyclase (AC) pathways. This causes macrophage infiltration and insulin resistance (orange).

Figure 3

Signaling pathway mediated by Escherichia coli lipopolysaccharides (LPSs). At the plasma membrane of target cells, LPS binds to TLR4 that recruits MyD88, facilitating the activation of IRAK and TRAF6. Subsequently, these proteins initiate the activation of MAPK and NF-κB pathways, involving JNK and IKK, respectively. This culminates in the activation of AP-1 and NF-κB transcription factors which leads to the production of inflammatory cytokines and oxidative stress. In the adipose tissue, LPS alters the production of specific adipokines and alters lipid metabolism, thereby inciting insulin resistance. Indeed, TLR activation abrogates the insulin signaling cascade through activation of kinases like JNK that promote serine phosphorylation of IRS-1 and disruption of the PI3K/Akt/AS160 pathway responsible for GLUT4 translocation to the plasma membrane, and thus glucose uptake. In parallel, in endothelial cells, LPS promotes the production of adhesion molecules, causing macrophage infiltration.

Figure 4

Gut bacteria catabolism of dietary fibers leading to the production of short-chain fatty acids (SCFAs). SCFAs are linear fatty acids comprising butyrate (C4), propionate (C3) and acetate (C2), resulting from the bacterial fermentation of dietary fibers. After gut absorption, SCFAs are delivered via the portal vein to reach the liver and then the systemic circulation. In the context of obesity, plasma SCFA levels decrease due to augmented fecal levels and reduced colonic barrier absorption. The physiological effects of SCFAs are mediated via G-protein coupled receptors that initiate intracellular signaling cascades, orchestrating health-enhancing impacts such as on the metabolic and endocrine functions of the adipose tissue.

Figure 5

Bacterial degradation of trimethylamine (TMA) for trimethylamine N-oxide (TMAO) formation. TMA is generated when the gut microbiota metabolize dietary carnitine, choline and choline-containing compounds. After gut absorption, at the hepatic level, TMA undergoes conversion into TMAO through flavin-dependent monooxygenase (FMO) isoforms 1 and 3. Then, TMAO enters the systemic circulation. During obesity, plasma TMAO levels are elevated. TMAO is associated with adipose tissue and endothelial inflammation, along with insulin resistance. The intracellular signaling pathway initiated by TMAO involves protein kinase R-like endoplasmic reticulum kinase (PERPK), leading to a pro-inflammatory status.

Figure 6

Catabolism of dietary tryptophan by gut bacteria leading to the production of indole derivatives. Dietary tryptophan undergoes catabolism by gut bacteria, giving rise to the synthesis of indole derivatives such as indole-3-acetic acid (IAA), indole-3-propionic acid (IPA) and indole (I). Indole derivatives are transported via the portal vein to the liver. In the liver, indole (I) is metabolized into indoxyl sulfate (IS). During obesity associated with gut bacteria dysbiosis, plasma levels of indole derivatives are reduced. Tryptophan-derived catabolites act as agonists for the aryl hydrocarbon receptor (AhR) that improves the metabolic and endocrine function of adipose tissue.

Figure 7

Overview of the molecular bridge based on adipokines and gut bacteria-derived metabolites that links adipose tissue dysfunction and obesity to gut microbiota dysbiosis.