Knockdown of Tlr4 in the Arcuate Nucleus Improves Obesity Related Metabolic Disorders

Yongli Zhao,Guohua Li,Ying Li,Zhengjuan Liu,Yuchuan Wang

doi:10.1038/s41598-017-07858-6

Abstract

High-fat diet-induced hypothalamic metabolic inflammation is emerging as a cause for the development of obesity. It is acknowledged that Toll-like receptor4 (TLR4) signaling plays a crucial role in triggering of the hypothalamic metabolic inflammation during the course of diet-induced obesity. Whether hypothalamic arcuate nucleus (ARC)-restricted TLR4 knockdown improves obesity-related metabolic disorders remains unexplored. In this study, we used TLR4 shRNA lentiviral particles to suppress the TLR4 expression in the hypothalamic ARC of diet-induced obese rat model by stereotaxic injection. Our results demonstrate that ARC-restricted TLR4 knockdown protects obese rats from diet-induced weight gain and energy intake, from diet-induced impaired glucose homeostasis and peripheral insulin resistance, and from high-fat diet-induced hepatic steatosis and adipocyte hypertrophy. Thus, we define ARC-restricted TLR4 knockdown as a potential strategy to combat metabolic disorders associated with obesity.

Highlights

The arcuate nucleus (ARC), which sits adjacent to the third ventricle in the mediobasal hypothalamus (MBH), contains two groups of neurons; one group is orexigenic and releases the neurotransmitters neuropeptide Y (NPY) and agouti-related peptide (AgRP) (NPY/AgRP neurons)
Our results demonstrated that down-regulation of toll-like receptor-4 (TLR4) expression, which was accompanied by the decreased expression of Tumor Necrosis Factor α (TNF-α), NPY and increased expression of POMC, in the hypothalamic ARC significantly alleviated diet-induced weight gain and energy intake, and improved peripheral glucose homeostasis, insulin sensitivity and abnormal gluconeogenesis
Our results found that the high-fat diet-induced hepatic steatosis and adipocyte hypertrophy were partially reversed after inhibition of TLR4 expression in the hypothalamic ARC, which was accompanied by the expression restoration of several glucose and lipid metabolism-related genes and inflammatory marker genes in the liver

Summary

Introduction

The arcuate nucleus (ARC), which sits adjacent to the third ventricle in the mediobasal hypothalamus (MBH), contains two groups of neurons; one group is orexigenic and releases the neurotransmitters neuropeptide Y (NPY) and agouti-related peptide (AgRP) (NPY/AgRP neurons). Recent study suggested that activation of TLR4 signaling in hypothalamus could trigger hypothalamic inflammatory response and lead to the resistance to anorexigenic signals, which has a crucial role in the genesis of obesity[10]. Milanski et al found that inhibition of hypothalamic TLR4 by intracerebroventricular injection of anti-TLR4 antibody improved hepatic insulin signal transduction and reduced steatosis and gluconeogenesis[11]. These studies suggest that TLR4 in hypothalamus might be an attractive target for therapeutics of diet-induced obese condition. We investigate whether down-regulation of TLR4 expression in hypothalamic ARC by stereotaxic injection of TLR4 shRNA lentiviral particles can improve the metabolic disorders in high-fat diet-induced obesity rat model

Methods

Results

Conclusion