Overexpression of SIRT1 in mouse forebrain impairs lipid/glucose metabolism and motor function.

Dongmei Wu,Xiang Gao,Qiwei Zhai,Xiao-Bing Yuan,Yifu Qiu,Vincent Laudet

doi:10.1371/journal.pone.0021759

Abstract

SIRT1 plays crucial roles in glucose and lipid metabolism, and has various functions in different tissues including brain. The brain-specific SIRT1 knockout mice display defects in somatotropic signaling, memory and synaptic plasticity. And the female mice without SIRT1 in POMC neuron are more sensitive to diet-induced obesity. Here we created transgenic mice overexpressing SIRT1 in striatum and hippocampus under the control of CaMKIIα promoter. These mice, especially females, exhibited increased fat accumulation accompanied by significant upregulation of adipogenic genes in white adipose tissue. Glucose tolerance of the mice was also impaired with decreased Glut4 mRNA levels in muscle. Moreover, the SIRT1 overexpressing mice showed decreased energy expenditure, and concomitantly mitochondria-related genes were decreased in muscle. In addition, these mice showed unusual spontaneous physical activity pattern, decreased activity in open field and rotarod performance. Further studies demonstrated that SIRT1 deacetylated IRS-2, and upregulated phosphorylation level of IRS-2 and ERK1/2 in striatum. Meanwhile, the neurotransmitter signaling in striatum and the expression of endocrine hormones in hypothalamus and serum T3, T4 levels were altered. Taken together, our findings demonstrate that SIRT1 in forebrain regulates lipid/glucose metabolism and motor function.

Highlights

Obesity is becoming a worldwide prevalent disease in recent years
Western blot analysis revealed that SIRT1 protein level was increased to 2.3-fold in striatum and 1.3-fold in hippocampus, but no obvious change in cerebral cortex of bitransgenic mice when compared with their littermate controls (Fig. 1C and D)
These results demonstrate that the bitransgenic mice exhibit a forebrain-specific SIRT1 overexpression

Summary

Introduction

Obesity is becoming a worldwide prevalent disease in recent years. Various diseases including diabetes, hepatic steatosis and atherosclerosis are associated with dysregulation of lipid metabolism. Our previous study showed that SIRT1 and resveratrol improved insulin sensitivity by repressing PTP1B transcription in hepatocytes or C2C12 myotubes [9]. Oral administration with SIRT1 activator resveratrol or SRT1720 in high-calorie-diet fed mice or diabetic mice improved hepatic, adipose and systemic insulin sensitivity, prevented the development of fatty liver and/or increased mitochondrial activity in the brown adipose tissue (BAT) and muscle [13,14,15]. All these studies demonstrate that SIRT1 plays crucial roles in lipid and glucose metabolism in peripheral tissues

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Conclusion