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).