3.1.2 Activating AMPK pathway
Adenosine 5’-monophosphate-activated protein kinase (AMPK) is a heterotrimer composed of three subunits, including α, β and γ, each of which is encoded by multiple genes such as α1, α2, β1, β2, γ1, γ2, γ3. AMPK integrates nutritional and hormonal signals in peripheral tissues and hypothalamus, thus regulating adipokines-mediated food intake, body weight, glucose and lipid homeostasis (Kahn, Alquier, Carling & Hardie, 2005). One of the widely accepted theories is that AMPK can be used as an energy sensor to adjust metabolic adaptation capability and energy metabolism when the ATP/AMP ratio is reduced under an IR state (Lin & Hardie, 2018). Inhibiting lipid synthesis, boosting fat oxidation, and increasing skeletal muscle glucose absorption are the three main ways that AMPK reduces IR (Hardie, 2013; Lindegaard et al., 2013). Specifically, accelerating fatty acid oxidation is considered as a main mechanism by which AMPK alleviates IR in peripheral tissue. In this process, AMPK primarily phosphorylates acetyl CoA carboxylase, attenuates palmitoyl-CoA transferase-1 (CPT1), promotes long-chain fatty acyl-CoA to enter the mitochondria, eventually stimulating fatty acid oxidation (Kahn, Alquier, Carling & Hardie, 2005). AMPK activity can also be inhibited by chronic low-grade inflammation; however, this effect is bidirectional (Day, Ford & Steinberg, 2017; Liong & Lappas, 2015). It is noted that AMPK and silent information regulator 1 (SIRT1) share many common signal factors and exert synergistic actions in alleviating IR. By deacetylating liver kinase B1 (LKB1), which is located upstream of AMPK, SIRT1 can activate AMPK. AMPK can also regulate SIRT1 by increasing nicotinamide adenine dinucleotide (NAD)/ reduced form of nicotinamide-adenine dinucleotide (NADH) ratio or nicotinamide phosphoribosyltransferase (NAMPT) expression (Rogacka et al., 2018).
Soy isoflavones (Supporting Information Table S2), a flavonoid compound, is a class of secondary metabolite produced in the soybean growth, also known as a phytoestrogen. Soy isoflavones regulated lipid metabolism in adipocytes via AMPK/sterol regulatory element binding protein-1 (SREBP-1) pathway. Soy isoflavones treatment significantly reduced body weight, adipocyte hypertrophy and excessive lipid accumulation in diet-induced obese (DIO) male rats (Tanet al., 2019).
Myricanol, a diarylheptane compound, is one of the active ingredients from Myrica rubra . It was proved to modulate skeletal muscle–adipose tissue crosstalk, reducing lipid accumulation, increasing WAT browning, and leading to improved mitochondrial function and insulin sensitivity (Shen, Liao, Zhang, Pan & Lin, 2019). The mechanisms were probably involved in AMPK/peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) pathway.
p-Coumaric acid is a ubiquitous flavonoid metabolite of plants. Anin vitro study indicated that p-coumaric acid promoted fatty acid β-oxidation, inhibited TG accumulation and enhanced 2-NBDG uptake in differentiated L6 skeletal muscle cells (Yoonet al., 2013). The data suggested that p-coumaric acid inhibited lipid accumulation and improved glucose uptake to exert health-promoting effects by activating AMPK expression.