3.1.4 Regulating PPARs
Peroxisome proliferator activated receptors (PPARs) are members of the
nuclear receptor superfamily of ligand-inducible transcription factors
and associated with metabolic homeostasis in the organism. There are
three subtypes in the PPARs: PPARα, PPARβ and PPARγ, each of which has
different functions and locations in vivo . PPARα is mainly
expressed in the liver, and promotes adaptive responses to fasting by
controlling fatty acid transport, fatty acid oxidation and ketogenesis.
PPARδ is highly expressed in skeletal muscle, regulates lipid and
glucose metabolism, and participates motor rection by regulating the
switch from glycolytic to oxidative muscle fibers.
PPARγ is a main regulator of
lipogenesis, increasing lipid storage, glucose metabolism and insulin
sensitivity via lipid-steal action (Ahmadian et al., 2013; Montaigne,
Butruille & Staels, 2021).
PPARα and PPARγ play critical roles in enhancing insulin sensitivity
(Gustafson, Hedjazifar, Gogg, Hammarstedt & Smith, 2015; Montaigne,
Butruille & Staels, 2021). Adiponectin-stimulated PPARα expression
could increase fatty-acid combustion and energy consumption, decrease TG
content in the liver and skeletal muscle, thus improving insulin
sensitivity. Meanwhile, lipolysis-derived fatty acid ligands-mediated
PPARα activation could promote mitochondrial activity and adipose tissue
energy metabolism. PPARγ, predominantly expressed in WAT and BAT, mainly
regulates IR through promoting adipose denaturation. It was found that
after deacetylation by SIRT1 in a NAD-dependent manner, PPARγ in WAT
promoted WAT browning, balanced energy storage and expenditure, thus
improving IR (Qiang et al., 2012). PPARγ agonists are prospective
medicines for alleviating IR. However, activated PPARγ might exhibit
contrary effects in different tissues. For example, short-chain fatty
acids (SCFAs) from dietary fiber fermentation prevented obesity and
enhanced insulin sensitivity by inhibiting PPARγ expression in the liver
and adipose tissues (den Besten et al., 2015).
Capsaicin (Supporting Information Table S3) is an effective alkaloid
from Capsicum annuum . Jiang et al. demonstrated that capsaicin
treatment could decrease body weight, adipose tissue weight, tumor
necrosis factor-α (TNF-α), MCP-1 and interleukin-6 (IL-6) expression and
improve glucose tolerance in DIO mice. Further studies suggested that
capsaicin might act through dual action on PPARγ/PPARα and transient
receptor potential vanilloid type-1 (TRPV-1) expression (Kang, Tsuyoshi,
Han, Kawada, Kim & Yu, 2010).
Naringenin is a Citrus flavonoid with remarkable therapeutic
effects on hyperlipemia, obesity and IR. A previous study demonstrated
that naringenin restored the grip strength, increased the insulin
sensitivity, and inhibited inflammation in C-26 tumor-bearing mice
(Snoke et al., 2021). As shown in a case study on a diabetic woman,
naringenin supplementation could reduce body weight, insulin content and
HOMA-IR, and further in vitro experiment demonstrated that
naringenin might act via regulating PPARα and PPARγ expression in human
subcutaneous adipose-derived stem cells (Murugesan, Woodard, Ramaraju,
Greenway, Coulter & Rebello, 2020).
Cinnamaldehyde, an aldehyde organic compound, is a yellow viscous liquid
mainly extracted from cinnamomum cassia . It was demonstrated that
cinnamaldehyde administration significantly reduced body weight gain,
attenuated adipocyte hypertrophy and hyperplasia in epididymal WAT and
promoted metabolic activity in
interscapular BAT, thus leading
to IR improvement in a time-dependent manner. Cinnamaldehyde exposure
also modulated the blood lipid profiles and lowered free fatty acids
(FFAs), leptin, TG, total
cholesterol (TC) and low-density lipoprotein cholesterol levels. The
mechanisms were partially related to up-regulation of PPARγ expression
(Zuo et al., 2017).
Luteolin is a flavonoid compound widely found in herbs, such asThymus mongolicus and Mentha hyplocalyx .
The ways that luteolin enhances IR
and T2DM are numerous. For example, it was reported that luteolin
enhanced hepatic insulin sensitivity by regulating the interaction
between the liver and adipose tissue (Kwon, Jung, Park, Yun & Choi,
2015). Likewise, luteolin was able to prevent hepatic and adipocyte
fibrosis and IR via the toll-like receptor (TLR) signaling pathway (Kwon
& Choi, 2018). By directly stimulating the PPARγ pathway or regulating
the insulin signaling cascades, luteolin may also improve the function
of insulin in adipocytes (Ding, Jin & Chen, 2010).