3.2 Inhibiting inflammation
Inflammation, characterized by swelling, redness, pain and fever, is helpful for dealing with external injuries and enhancing immune system aggressiveness and tissue repair and remodeling. However, long-term chronic low-grade inflammation could lead to significant adverse consequences (Gustafson, Hedjazifar, Gogg, Hammarstedt & Smith, 2015). Obesity-induced IR, mainly triggered by macrophages infiltration in WAT, is characterized by chronic low-grade tissue inflammation in the organism. Stimulated adipocytes could secrete cytokines, which would travel to peripheral tissue and result in localized inflammation and IR in the liver, skeletal muscle, etc. (Johnson & Olefsky, 2013). Thus, inhibiting the inflammatory cytokines and signaling pathways, such as IL-6, TNF-α, JNK and NF-κB might contribute to alleviation of IR and its associated disorders.
3.2.1 Inhibiting NF- κB pathway
NF-κB family transcription factors are the major regulators of immune and inflammatory processes in response to injuries and infections in the organism. NF-κB pathway is one of the classical inflammation-related signaling pathways, which plays an important role in IR-related inflammation and exhibits different effects in different tissues. For example, the activated NF-κB pathway in hypothalamus mediated leptin resistance (Osborn & Olefsky, 2012), promoted pancreatic fibrosis via NF-κB-TGF-β1 crosstalk (Yan, Ren, Kou, Meng & Li, 2012), and induced muscle atrophy by inhibitor of kappa B kinase (IKK)/NF-κB activation (Samuel & Shulman, 2012). In most cases for obesity-induced IR, NF-κB activation is mainly caused by excessive lipid accumulation and fatty acid extravasation in adipocytes (Chen, Chen, Wang & Liang, 2015). Usually, NF-κB is packaged by its inhibitor IκB and formed into a complex stored in cytoplasm. NF-κB complex is a classic IKK target, in which IKK phosphorylates IκBα subunit and leads to proteasomal degradation, eventually resulting in NF-κB nuclear translocation (including p50 and p65 subunits) and pro-inflammatory gene expression (Samuel & Shulman, 2012). Various studies have revealed that blocking NF-κB pathway is a prospective strategy to suppress inflammation and consequently alleviate IR. In support, aspirin was found to improve IR by blunting NF-κB activation (Amy Fleischman, Steven E. Shoelson, Raquel Bernier & Allison B. Goldfine, 2008).
β-sitosterol (Fig 3) is a bioactive constituent rich in vegetable oils or seeds. A published study showed that β-sitosterol treatment for 30 days significantly prevented body weight gain, decreased SREBP-1c and PPAR-γ contents in serum and inhibited TNF-α and IL-6 expression in adipose tissues of T2DM rats (Jayaraman et al., 2021). Further study suggested that the effects of β-sitosterol were probably achieved by inhibiting IKKβ/NF-κB and JNK pathways.
Stevioside (Supporting Information Table S5), a tetracyclic diterpenoid compound derived from Stevia rebaudiana Bertoni., has numerous beneficial effects on diabetic patients. For example, Wang et al. found that stevioside was able to improve glucose tolerance and whole-body insulin sensitivity, decrease pro-inflammatory cytokines production and macrophages infiltration in HFD-induced IR mice by inhibiting NF-κB pathway (Wang et al., 2012).
Troxerutin (also named vitamin P4), one of the derivatives of rutin, is a flavonoid compound from Sophora japonica . By inhibiting ROS generation and ERS-mediated NOD activation, troxerutin showed excellent antioxidant effects. A published study demonstrated that troxerutin administration improved hyperglycemia in diabetic rats, which was at least partially achieved by its antioxidant capacities (Xing, Xiang & Li, 2020).
3.2.2 SuppressingNLRP3 inflammasome activity
NLRP3 inflammasome, a group of protein complex composed of NLRP3, apoptosis-associated spot-like protein containing CARD and pro-caspase-1, plays a central role in the progression and development of obesity and IR (Wan, Xu, Lu, Zhu, Yu & Li, 2015). Various factors including hypoxia, β-cell products islet amyloid polypeptide, uric acid, glucose, FFAs, ceramide, palmitate, NF-κB and AMPK were involved in NLRP3 inflammasome activity (Rohm, Meier, Olefsky & Donath, 2022; Strowig, Henao-Mejia, Elinav & Flavell, 2012; Wan, Xu, Lu, Zhu, Yu & Li, 2015). Especially, NLRP3 inflammasome was reported to act by regulating the pro-inflammatory cytokines (Strowig, Henao-Mejia, Elinav & Flavell, 2012). For instance, NLRP3 inflammasome-induced IL-1β accumulation could induce β-cells death or dysfunction and promote chemokines production in a(n) autocrine or paracrine manner (Rohm, Meier, Olefsky & Donath, 2022; Strowig, Henao-Mejia, Elinav & Flavell, 2012). IL-18 levels in serum of insulin resistant patients were also significantly up-regulated, which was attributed to the activation of NLRP3 inflammasome (Donath, Dinarello & Mandrup-Poulsen, 2019; Lee, Kim, Kim, Shong, Ku & Jo, 2013). These evidences indicated that NLRP3 inflammasome might be a reasonable target in regulating the initiation and development of various autoinflammatory and autoimmune diseases, providing a feasible direction to develop novel drugs for IR treatment. Numerous studies have confirmed this perspective. For example, glibenclamide improved glucose levels and β-cells functions in T2DM patients by suppressing NLRP3 inflammasome-mediated IL-1β release (Lee, Kim, Kim, Shong, Ku & Jo, 2013; Strowig, Henao-Mejia, Elinav & Flavell, 2012).
Isoliquiritigenin (Supporting Information Table S6), a flavonoid compound exacted fromGlycyrrhiza uralensis Fisch., is a potential candidate for inflammatory disease by targeting NLRP3 inflammasome. It was found that isoliquiritigenin intervention potently alleviated HFD-induced obesity, hepatic steatosis, lipid metabolic disorder and IR in mice by preventing NLRP inflammasome activation (Honda et al., 2014).
Betaine, a quaternary ammonium base alkaloid, is a metabolite of choline in animals, and also an active ingredient of Lycium chinenseMiller. and most leguminous plants. Betaine could reduce NLRP3 inflammasome activity by activating PI3K/AKT pathway and suppressing FOXO1 phosphorylation, thus leading to the inhibition of the inflammatory responses and improvement of IR in diabetes (Kim et al., 2017).
Quercetin is a natural flavonoid compound widely extracted from the stems, barks, flowers, leaves, buds, seeds and fruits of many plants. It has been demonstrated that quercetin has central nervous system activity, which leads to reduced AMPK activation, thioredoxin-interacting protein overexpression, and glutamine-glutamate cycle dysfunction in the hypothalamus of high fructose-fed rats (Zhang et al., 2014). Simultaneously, quercetin could ameliorate high fructose-caused hypothalamic inflammatory lesions by inhibiting NF-κB pathway, NLRP3 inflammasome activation and IL-1β maturation. Given these, quercetin might have potential for improving IR and hyperlipidaemia.
3.3 Reversinggut microbiota dysbiosis
Human gut microbiota comprises trillions of bacteria that constitutes the largest intestinal microecosystem in the organism. A growing number of evidences have proven that the gut microbiota compositions in lean and obese populations are significantly different (Tsukumo, Carvalho, Carvalho & Saad, 2015). The changes in gut microbiota composition and structure, such as the Firmicutes/Bacteroides ratio alteration, could affect intestinal function, host metabolism and signal transduction pathways, resulting in obesity, IR and eventually diabetes (He et al., 2022; Xie, Zhao & Chen, 2021).
Effects of the gut microbiota on the organism function are mainly achieved by two aspects. The gut microbiota can increase the energy intake from indigestible polysaccharides (Tsukumo, Carvalho, Carvalho & Saad, 2015). Meanwhile, the gut microbiota-derived metabolites could act on the organism. For example, the endogenous endotoxin (such as lipopolysaccharide) secreted by gram-negative bacteria in gut microbiota could lead to metabolic inflammation, obesity and IR through activating TLR4 (Saad, Santos & Prada, 2016). The gut microbiota could also release SCFAs, amino acids derivatives and secondary bile acids, which positively regulates the lipid and glucose metabolism of the host (Heet al., 2022). Growing evidences have suggested that the pathways by which the gut microbiota alleviates the metabolic syndromes include regulation of TMAO pathway, mammalian target of rapamycin (mTOR) pathway and miRNAs expression (Heet al., 2022; Xie, Zhao & Chen, 2021). Hence, adjusting the gut microbiota is a potential way to alleviate IR. Yang et al. showed that exercise improved glucose metabolism and insulin sensitivity, partially by modulating gut microbiota compositions in patients (Yang, Lin, Lin & Xu, 2020).
Curcumin was proved to ameliorate hepatic steatosis and IR in HFD-fed obese mice by decreasing Firmicutes/Bacteroidetes ratio and endotoxin-producing Desulfovibrio bacteria abundance, increasing Akkermansia abundance and SCFAs-producing bacteria abundance and reversing gut microbiota dysbiosis (Li et al., 2021).
Astragaloside IV (Fig 4), a triterpenoid saponin compound, is one of the major active components of Astragalus membranaceus . Gong et al. hypothesized that astragaloside IV probably improved IR by modulating the gut microbiota compositions (Gong et al., 2021). It was considered that HG and HFD feeding could lead to excess ROS generation by inducing oxidative stress and resulting in significant gut microbiota disorders. Then, the signaling pathways related to insulin transduction were inhibited and subsequently IR occurred. Astragaloside IV exhibited the ability to scavenge ROS, balance the gut microbiota structures and activate the insulin signaling pathways, thus ameliorating IR symptoms. Additionally, astragaloside IV could be metabolized into astragalus alcohol by gut microbiota, further contributing to sodium-dependent glucose transporters 2 expression reduction and T2DM improvement.
Qiao et al. found that resveratrol treatment showed anti-obesity effects by improving HFD-induced gut microbiota disorders, as evidenced by the reduced Firmicutes/Bacteroidetes ratio (Qiao, Sun, Xia, Tang, Shi & Le, 2014). Further assays demonstrated resveratrol administration significantly increased fasting-induced adipocyte factor expression (Fiaf , a key gene negatively regulated by the intestinal microflora), thereby decreasing the expression levels of genes associated with fatty acid synthesis and lipogenesis.
Oleanolic acid (Supporting Information Table S7), a natural pentacyclic triterpenoid consisting in various plants in a free or ligand form, is rich in the fruits of Ligustrum lucidum . Effects of oleanolic acid on gut microbiota disorders were confirmed by a previous study (Xue et al., 2021). Briefly, oleanolic acid supplementation markedly restored HFD-induced metabolic disturbances, IR and hepatic steatosis in rats. HFD-induced intestinal barrier dysfunction and endotoxin-mediated TLR4-related pathways were modulated by oleanolic acid addition, thus inhibiting endotoxemia and systemic inflammation and balancing the gut-liver axis homeostasis. Besides, oleanolic acid treatment effectively reduced Firmicutes/Bacteroidetes ratio and increased butyrate-producing bacteria abundance, implying that the gut microbiota compositions in HFD-fed rats were significantly remodeled by oleanolic acid intervention.