The chaperone GRP78/BiP (glucose regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to ER stress. The aim of this study was to investigate the role of hypothalamic GRP78 on energy balance, with particular interest on thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and thapsigargin-treated rats and by combining metabolic, histologic, physiologic, pharmacologic, thermographic and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high fat diet (HFD) or centrally treated with thapsigargin, displayed hypothalamic ER stress, while genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus (VMH) was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were feeding and leptin independent, but related to increased thermogenic activation of brown adipose tissue (BAT) and induction of browning in WAT, and could be reversed by antagonism of beta 3 adrenergic receptors (β3-AR). This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.
- Received November 8, 2015.
- Accepted September 7, 2016.
- © 2016 by the American Diabetes Association.