The Anti-Obesity and Anti-Steatotic Effects of Chrysin in a Rat Model of Obesity Mediated through Modulating the Hepatic AMPK/mTOR/lipogenesis Pathways

Abstract

Background: Obesity is a complex multifactorial disease characterized by excessive adiposity, and is linked to an increased risk of nonalcoholic fatty liver disease (NAFLD). Flavonoids are natural polyphenolic compounds that exert interesting pharmacological effects as antioxidant, anti-inflammatory, and lipid-lowering agents. In the present study, we investigated the possible therapeutic effects of the flavonoid chrysin on obesity and NAFLD in rats, and the role of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways in mediating these effects. Method: Thirty-two Wistar male rats were divided into two groups: the control group and the obese group. Obesity was induced by feeding with an obesogenic diet for 3 months. The obese rats were subdivided into four subgroups, comprising an untreated group, and three groups treated orally with different doses of chrysin (25, 50, and 75 mg/kg/day for one month). Results revealed that chrysin treatment markedly ameliorated the histological changes and significantly and dose-dependently reduced the weight gain, hyperglycemia, and insulin resistance in the obese rats. Chrysin, besides its antioxidant boosting effects (increased GSH and decreased malondialdehyde), activated the AMPK pathway and suppressed the mTOR and lipogenic pathways, and stimulated expression of the genes controlling mitochondrial biogenesis in the hepatic tissues in a dose-dependent manner. In conclusion, chrysin could be a promising candidate for the treatment of obesity and associated NAFLD, aiding in attenuating weight gain and ameliorating glucose and lipid homeostasis and adipokines, boosting the hepatic mitochondrial biogenesis, and modulating AMPK/mTOR/SREBP-1c signaling pathways.

Maternal and paternal obesity differentially reprogram the ovarian mitochondrial biogenesis of F1 female rats

“…Obesity is associated with reduced AMPK activation, concomitant with alterations in glycolysis, insulin sensitivity, hepatic lipid metabolism and inflammation 39 . Oriquat et al, 2023 showed that HFD induced significant downregulation of the expression of AMPK and its upstream activating kinase (LKB1), and p-AMPK and LKB1 protein levels 40 . The role of AMPK in ovarian maturation was confirmed in the present study by the correlation data which indicated that AMPK showed a positive correlation with the number of primordial, primary, and antral follicles and negatively correlated with the number of cystic follicles and histologic lesion score.…”

Exploring the Prospective Role of Propolis in Modifying Aging Hallmarks

“…In a parallel manner, a 4-week regimen of chrysin treatment in rats successfully reversed glucose elevation, inflammation, and the decline in serum insulin levels associated with aging, indicating that chrysin helps preserve islet function [ 248 ]. The research conducted by Oriquat et al revealed that chrysin exhibited notable effects in mitigating weight gain and rectifying hyperglycemia, insulin resistance, and dyslipidemia while simultaneously improving adipocytokine levels in rats with metabolic disturbances induced by a high-fat diet [ 249 ]. Moreover, the authors provided evidence that chrysin regulates hepatic signaling by activating the AMPK pathway and inhibiting the mTOR and lipogenic pathways, resulting in anti-obesity and antisteatotic effects [ 249 ].…”

“…The research conducted by Oriquat et al revealed that chrysin exhibited notable effects in mitigating weight gain and rectifying hyperglycemia, insulin resistance, and dyslipidemia while simultaneously improving adipocytokine levels in rats with metabolic disturbances induced by a high-fat diet [ 249 ]. Moreover, the authors provided evidence that chrysin regulates hepatic signaling by activating the AMPK pathway and inhibiting the mTOR and lipogenic pathways, resulting in anti-obesity and antisteatotic effects [ 249 ]. The prevalence of nonalcoholic fatty liver disease (NAFLD) is 39% among individuals aged 40 to 50 and exceeds 40% in those aged 70 and above [ 250 ].…”

Recent Insights into the Biomarkers, Molecular Targets and Mechanisms of Non-Alcoholic Steatohepatitis-Driven Hepatocarcinogenesis

“…It has been recently reported that natural products, including phenols, flavonoids, glycosides, quinones, terpenoids, pyrazines, alkaloids, and phenylpropanoids, have antioxidant, energy-producing, anti-inflammatory, anti-apoptotic, and anti-aging effects, which mainly influence the AMPK/Nrf2/mTOR, Nrf2/HO-1, NAMPT/NAD(+)/SIRT, AMPK/SIRT1/PGC-1alpha and PKCs/PARPs/NF-kB signaling pathways, thereby regulating NAD(+) metabolism to prevent and treat NAFLD [ 117 ]. Hepatoprotective effects, caused by the inhibition of PI3K/Akt/mTOR signaling and effective alleviation of oxidative stress damage and ER stress induced by excessive lipid accumulation in hepatocytes, and activation of autophagy were observed for agonists of AMPK thymoquinone [ 118 ] and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) [ 119 ], agonist of GLP-1/glucagon cotadutide [ 120 ], an antagonist of sphingosine 1-phosphate receptor 2 (S1PR2) JTE-013 [ 26 ], activator of PI3K, autophagy-related genes (ATG) and agonist of Nrf2, PPARα and hemeoxygenase-1 (HO-1) pterostilbene [ 121 ], flavonoid with antioxidant properties involving CYP7A1, quercetin [ 122 ], Pueraria flavonoids [ 92 ], a novel gerotherapy compound, BIOIO-1001 [ 123 ], a natural nonenzymatic antioxidant with low toxicity schisandrin B (Sch B) [ 124 ], H1-antihistamines (AHs) [ 125 ], fat soluble polyphenol Tanshinone IIA (TsIIA) [ 126 ], purendan (PRD) [ 127 ], down-regulating the expression of p-mTOR, p-S6K1 and SREBP-1c, chrysin [ 128 ], red pepper seed extract (RPS) [ 129 ], Gardenia Fructus (GF) extracts [ 130 ], curcumin [ 131 ], and magnesium [ 132 ].…”