Reduction of Hypothalamic Endoplasmic Reticulum Stress Activates Browning of White Fat and Ameliorates Obesity

Abstract

The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, 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 or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.

Cinnamaldehyde Ameliorates Diet-Induced Obesity in Mice by Inducing Browning of White Adipose Tissue

“…Due to the similarity of the structures of the two adipose tissue types, they can mutually trans-differentiate into the other type. Based on accumulating evidence, morphological transition from the WAT phenotype to the BAT phenotype, a process known as “browning”, may facilitate the treatment of obesity [31]. The conversion of WAT to BAT is initiated by various conditions and agents, such as cold exposure [32] and the PPAR agonist rosiglitazone [33, 34].…”

Traveling from the hypothalamus to the adipose tissue: The thermogenic pathway

“…High levels of hypothalamic ceramides have been shown to be lipotoxic, by promoting ER stress in the VMH and reducing the BAT sympathetic tone which impairs the thermogenic process [98]. Overexpression of the chaperone glucose related protein 78 (GRP78) in the VMH, decreases ER stress thereby promoting BAT thermogenesis and browning of WAT causing weight loss and improvement in the metabolic phenotype of diet-induced obese rats in manner independent of feeding [99], [100]. These data suggest that modulation of hypothalamic ER stress could be a promising therapy to treatment of obesity and associated metabolic alterations.…”

The biochemical alterations underlying post-burn hypermetabolism

“…These changes were accompanied by reductions in other ER stress markers such as p-IRE and peIF2α and increases in BAT darkness and temperature [75] and [76]. ATF4 and CHOP knock out mice have also been reported to induce browning while TLR4 activated browning inhibition occurred coincident with increased ER stress markers [77] and [78].…”