Genetic Targeting of GRP78 in the VMH Improves Obesity Independently of Food Intake.

Laura Liñares-Pose,Edward Milbank,Carlos Diéguez,Miguel López,Cristina Contreras,Ismael González-García,Dolores Prieto,Patricia Seoane-Collazo,Claudia Rodríguez,Ánxela Estévez-Salguero,Eva Rial-Pensado,Noelia Martinez-Sánchez,Rubén Nogueiras

doi:10.3390/genes9070357

Abstract

Recent data have demonstrated that the hypothalamic GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates brown adipose tissue (BAT) thermogenesis by acting downstream on AMP-activated protein kinase (AMPK). Herein, we aimed to investigate whether genetic over-expression of GRP78 in the ventromedial nucleus of the hypothalamus (VMH: a key site regulating thermogenesis) could ameliorate very high fat diet (vHFD)-induced obesity. Our data showed that stereotaxic treatment with adenoviruses harboring GRP78 in the VMH reduced hypothalamic endoplasmic reticulum ER stress and reversed vHFD-induced obesity. Herein, we also demonstrated that this body weight decrease was more likely associated with an increased BAT thermogenesis and browning of white adipose tissue (WAT) than to anorexia. Overall, these results indicate that the modulation of GRP78 in the VMH may be a target against obesity.

Highlights

Energy balance can be modulated by peripheral signals acting on the central nervous system (CNS), notably on the hypothalamus [1,2,3]
We evaluated the impact of ventromedial nucleus of the hypothalamus (VMH) glucose regulated protein 78 kDa (GRP78) overexpression on glucose insulin sensitivity in standard laboratory (STD) and very high fat diet (vHFD) rats
This study highlights the role of the chaperone GRP78 in the VMH, a major hypothalamic the modulation of brown fat thermogenesis and browning [3,6,7]

Summary

Introduction

Energy balance can be modulated by peripheral signals acting on the central nervous system (CNS), notably on the hypothalamus [1,2,3]. There has been a growing interest in mechanisms activating the thermogenic process, on the central control of the brown adipose tissue (BAT) activity [3,4,5,6,7]. Even more recently, browning—a process described as the trans-differentiation of white into beige/brite adipocytes in the white adipose tissue (WAT)—has been recognized to be a therapeutic target to reduce body weight through the increase of energy expenditure [8,9,10,11]. Increasing evidence has revealed a strong interaction between hypothalamic endoplasmic reticulum (ER) stress and obesity occurrence.

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Methods

Conclusion