3.1.5 Activating SIRT1
SIRT1, a member of Sirtuins, is the major nuclear NAD-dependent deacetylase in vivo . SIRT1 is involved in the regulation of many processes in the organism, such as mitochondrial biogenesis, inflammation, intracellular metabolism, stress resistance, apoptosis and glucose homeostasis (Szkudelski & Szkudelska, 2015). The mechanisms by which SIRT1 alleviates IR include attenuating mitochondrial dysfunction via the SIRT1–SIRT3–mitochondrial complex I pathway (Zhang et al., 2015), inhibiting protein tyrosine phosphatase 1b (PTP1B, a negative regulator of the insulin signaling pathway) (Sun et al., 2007), regulating macrophages infiltration and polarization (Hui et al., 2017), suppressing inflammatory responses in macrophages (Yoshizaki et al., 2010). In addition, SIRT1 is connected to BAT activity and WAT browning. In support, Xu et al. found that SIRT1 deficiency significantly promoted BAT degeneration in HFD-challenged mice, resulting in IR aggravation (Xu et al., 2016). Another study that demonstrated how SIRT1 significantly increased WAT browning by deacetylating PPAR on Lys268 and Lys293 further confirmed this finding (Li Qiang & Yingming Zhao, 2012). In addition to PPARγ, there are numerous additional substrates for SIRT1 deacetylation, including FOXO1, nuclear factor kappa-B (NF-κB) P65, PGC-1α, which are all closely associated with IR. Hence, activation of SIRT1 might be a prospective target for selecting medicine to improve IR.
Resveratrol (Supporting Information Table S4), a non-flavonoid polyphenolic organic compound, is an antitoxin produced by plants being irritated. Cote et al. demonstrated that resveratrol improved hypothalamic insulin sensitivity by activating SIRT1 and AMPK in duodenum to initiate a gut–brain–liver neuronal axis in rats (Cote et al., 2015).
Berberine, a quaternary ammonium alkaloid, is a main effective constituent of Coptis chinensis . It was evidenced that berberine alleviated HG-induced IR by stimulating liver kinase B1/AMPK/PGC1α pathway in the liver of mice (Li, Wang, Shen, Bai & Xu, 2020). By targeting the MEKK1/MEK/ERK pathway, Berberine could alleviate TNF-α-induced IR in hepatocyte (Li et al., 2022). Berberine also potently promoted adipose tissue remodeling and thermogenesis by regulating PPARγ deacetylation via AMPK/SIRT1 pathway (Xu et al., 2021). Furthermore, a previous study suggested that berberine could improve insulin signaling transduction by reducing ERS (Wang, Lu, Xu & Dong, 2010).
Patchouli alcohol, a tricyclic sesquiterpene, naturally exists inPogostemon cablin Benth. Patchouli alcohol could ameliorate inflammation, skeletal muscle IR and hepatic steatosis, and improve systematic glucose tolerance and insulin sensitivity in HFD-induced mice by up-regulating fatty acid oxidation via liver kinase B1/AMPK/SIRT1-dependent pathway (Pyun et al., 2021).