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Genes (Basel). 2018 Jul 17;9(7). pii: E357. doi: 10.3390/genes9070357.

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

Author information

1
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. laura.linares@usc.es.
2
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. laura.linares@usc.es.
3
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. eva.pensado@usc.es.
4
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. eva.pensado@usc.es.
5
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. anxela.estevez@usc.es.
6
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. anxela.estevez@usc.es.
7
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. ed.milbank@usc.es.
8
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. ed.milbank@usc.es.
9
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. ismael.gonzalez@usc.es.
10
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. ismael.gonzalez@usc.es.
11
Department of Physiology, School of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain. claudrod@ucm.es.
12
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. patricia.seoane@usc.es.
13
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. patricia.seoane@usc.es.
14
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. noelia.martinez@usc.es.
15
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. noelia.martinez@usc.es.
16
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. ruben.nogueiras@usc.es.
17
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. ruben.nogueiras@usc.es.
18
Department of Physiology, School of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain. dprieto@farm.ucm.es.
19
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. carlos.dieguez@usc.es.
20
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. carlos.dieguez@usc.es.
21
Department of Physiology, School of Pharmacy, Universidad Complutense de Madrid, 28040 Madrid, Spain. criscont@ucm.es.
22
Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria de Santiago de Compostela, 15782 Santiago de Compostela, Spain. m.lopez@usc.es.
23
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. m.lopez@usc.es.

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.

KEYWORDS:

ER stress; GRP78; brown adipose tissue; browning; hypothalamus; thermogenesis; white adipose tissue

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