POCU1b, the n-Butanol Soluble Fraction of Polygoni Cuspidati Rhizoma et Radix, Attenuates Obesity, Non-Alcoholic Fatty Liver, and Insulin Resistance via Inhibitions of Pancreatic Lipase, cAMP-Dependent PDE Activity, AMPK Activation, and SOCS-3 Suppression.

Junghyun Kim,Joo-Hwan Kim,Jin Sook Kim,Kyuhyung Jo,Chan-Sik Kim,Ik Soo Lee

doi:10.3390/nu12123612

Abstract

This study investigated the effects of the n-BuOH soluble fraction of Polygoni Cuspidati 80% ethanol extract (POCU1b) on high-fat diet (HFD)-induced obesity, non-alcoholic fatty liver (NAFL), and insulin resistance (IR) to find a safe and more effective agent. HPLC profiling of POCU1b identified seven marker compounds. POCU1b increased glycerol release, cyclic adenosine monophosphate (cAMP) level, and inhibited phosphodiesterase (PDE) activity. Seven weeks of POCU1b treatment decreased body weight gain, weight and adipocyte size in fat tissues, serum lipids, and triglyceride and lipid droplets in the livers of HFD-fed rats. POCU1b improved blood glucose, insulin sensitivity, and impaired insulin secretion in the pancreas. Further, POCU1b ameliorated adiponectin, leptin, IL-6 and TNF-α levels, increased AMPK and p-ACC expression, activated CPT-1 activity, and suppressed FAS mRNA, SOCS-3 protein expression, and NF-κB DNA-binding activity. When compared with the Xenical®-treated group, a positive group, the action of POCU1b on body weight was more effective than that of Xenical. POCU1b did not show side effects, such as oily spotting and loss of appetite. These results suggest that POCU1b possesses therapeutic or preventive potential for obesity, NAFL and IR via inhibitions of pancreatic lipase and cAMP-dependent PDE activity, AMPK activation, and SOCS-3 suppression, without oily spotting and loss of appetite.

Highlights

Obesity is a growing public health concern worldwide, and excess fat deposition in the liver is accompanied by histological alterations, varying from simple hepatic steatosis and non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), that can progress to cirrhosis and liver
We investigated whether seven weeks of POCU1b treatment attenuates obesity, NAFL, and insulin resistance (IR) using high-fat diet (HFD)-fed rats, by measuring the body weight, fat weight, adipocyte size, liver TG levels, and insulin sensitivity, and determining the mRNA
Effectively obesity‐induced non‐alcoholic fatty liver (NAFL), and insulin byPOCU1b using rats infused with lipid emulsion, HFD‐induced and oral an enzymatic assay

Summary

Introduction

Obesity is a growing public health concern worldwide, and excess fat deposition in the liver is accompanied by histological alterations, varying from simple hepatic steatosis and non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), that can progress to cirrhosis and liverNutrients 2020, 12, 3612; doi:10.3390/nu12123612 www.mdpi.com/journal/nutrientsNutrients 2020, 12, 3612 cancer, and is a risk factor of insulin resistance (IR) [1]. The inhibition of the digestion and absorption of dietary fat has been used as a strategy to treat obesity. Pancreatic lipase is the most important enzyme for the digestion of dietary triglycerides (TGs) [4]. Lipolysis is an important mechanism to reduce body fat, and involves the lipase-catalyzed hydrolysis of TG to glycerol and free fatty acids. The lipolytic effects of phosphodiesterase (PDE) inhibitors are mediated by cyclic adenosine monophosphate (cAMP)-dependent PDE inhibiting, and the subsequent increase in cAMP levels stimulates hormone-sensitive lipase (HSL) to reduce the lipogenesis [5]. Sibutramine, rimonabant, and orlistat (Xenical® ) are approved by the US FDA for the treatment of obesity. A potent natural inhibitor of pancreatic lipases, promotes body weight loss and reduces the incidence of diabetes by nearly 40% in obese people [7]. There clearly is an urgent need for safer and more effective anti-obesity agents for long-term treatment

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