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.