Ganoderma lucidum Extract Reduces Insulin Resistance by Enhancing AMPK Activation in High-Fat Diet-Induced Obese Mice.

Hyeon A Lee,Jae-Han Cho,Seong Ho Choi,Qonita Afinanisa,Gi-Hong An,Jae-Gu Han,Hyo Jeung Kang,Hyun-A Seong

doi:10.3390/nu12113338

Abstract

Ganoderma lucidum is used widely in oriental medicine to treat obesity and metabolic diseases. Bioactive substances extracted from G. lucidum have been shown to ameliorate dyslipidemia, insulin resistance, and type 2 diabetes in mice via multiple 5′ AMP-activated protein kinase (AMPK)-mediated mechanisms; however, further studies are required to elucidate the anti-obesity effects of G. lucidum in vivo. In this study, we demonstrated that 3% G. lucidum extract powder (GEP) can be used to prevent obesity and insulin resistance in a mouse model. C57BL/6 mice were provided with a normal diet (ND) or a high-fat diet (HFD) supplemented with 1, 3, or 5% GEP for 12 weeks and the effect of GEP on body weight, liver, adipose tissue, adipokines, insulin and glucose tolerance (ITT and GTT), glucose uptake, glucose-metabolism related proteins, and lipogenesis related genes was examined. GEP administration was found to reduce weight gain in the liver and fat tissues of the mice. In addition, serum parameters were significantly lower in the 3% and 5% GEP mice groups than in those fed a HFD alone, whereas adiponectin levels were significantly higher. We also observed that GEP improved glucose metabolism, reduced lipid accumulation in the liver, and reduced adipocyte size. These effects may have been mediated by enhanced AMPK activation, which attenuated the transcription and translation of lipogenic genes such as fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and sterol regulatory element-binding protein-1c (SREBP1c). Moreover, AMP-activated protein kinase (AMPK) activation increased acetyl-CoA carboxylase (ACC), insulin receptor (IR), IR substrate 1 (IRS1), and Akt protein expression and activation, as well as glucose transporter type 1/4 (GLUT1/4) protein production, thereby improving insulin sensitivity and glucose metabolism. Together, these findings demonstrate that G. lucidum may effectively prevent obesity and suppress obesity-induced insulin resistance via AMPK activation.

Highlights

Obesity is a metabolic disease characterized by excess lipid deposition [1,2] that can increase adipose tissue mass by increasing the number or size of adipocytes.Nutrients 2020, 12, 3338; doi:10.3390/nu12113338 www.mdpi.com/journal/nutrientsAdipocyte hypertrophy can dysregulate adipocyte hormone signaling and increase the secretion of inflammatory cytokines, leading to insulin resistance and chronic low-grade inflammation, among other complications [3,4]
We investigated G. lucidum extract powder (GEP) effect on glucose metabolism by assessing glucose uptake in the administered with insulin, GEP treatment dose-dependently improved glucose uptake (Figure 6A) and presence and absence of human insulin in white adipose tissues (WAT) from 1%, 3% and 5% GEP treated high-fat diet (HFD)-induced insulin receptor (IR), IR substrate 1 (IRS1), and AKT serine/threonine kinase 1 (AKT1) phosphorylation, obese mice, and the expression and activation of proteins involved in insulin signaling
Levels as well as AKT1 activation at phosphorylation sites T308 and S473 (Figure 6B,C). These findings indicate that GEP supplementation may improve glucose metabolism

Summary

Introduction

Obesity is a metabolic disease characterized by excess lipid deposition [1,2] that can increase adipose tissue mass by increasing the number (hyperplasia) or size (hypertrophy) of adipocytes.Nutrients 2020, 12, 3338; doi:10.3390/nu12113338 www.mdpi.com/journal/nutrientsAdipocyte hypertrophy can dysregulate adipocyte hormone signaling and increase the secretion of inflammatory cytokines, leading to insulin resistance and chronic low-grade inflammation, among other complications [3,4]. AMPK regulates lipid metabolism via multiple signaling pathways. AMPK has been reported to inhibit sterol regulatory element-binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor γ (PPARγ), which are the master regulators of lipogenesis and adipogenesis, respectively [9]. ACC is an enzyme that converts acetyl-CoA into malonyl-CoA, a precursor of fatty acid synthesis that inhibits fatty acid oxidation in mitochondria [8]; the inhibition of ACC by AMPK reduces fatty acid synthesis and increases fatty acid oxidation [10,11]. AMPK has been found to activate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and thereby stimulate mitochondrial biogenesis, leading to increased fatty acid oxidation [8].

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