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.