GRP78 plays an essential role in adipogenesis and postnatal growth in mice

Abstract

To investigate the role of GRP78 in adipogenesis and metabolic homeostasis, we knocked down GRP78 in mouse embryonic fibroblasts and 3T3-L1 preadipocytes induced to undergo differentiation into adipocytes. We also created an adipose Grp78-knockout mouse utilizing the aP2 (fatty acid binding protein 4) promoter-driven Cre-recombinase. Adipogenesis was monitored by molecular markers and histology. Tissues were analyzed by micro-CT and electron microscopy. Glucose homeostasis and cytokine analysis were performed. Our results indicate that GRP78 is essential for adipocyte differentiation in vitro. aP2-cre-mediated GRP78 deletion leads to lipoatrophy with ∼90% reduction in gonadal and subcutaneous white adipose tissue and brown adipose tissue, severe growth retardation, and bone defects. Despite severe abnormality in adipose mass and function, adipose Grp78-knockout mice showed normal plasma triglyceride levels, and plasma glucose and insulin levels were reduced by 40-60% compared to wild-type mice, suggesting enhanced insulin sensitivity. The endoplasmic reticulum is grossly expanded in the residual mutant white adipose tissue. Thus, these studies establish that GRP78 is required for adipocyte differentiation, glucose homeostasis, and balanced secretion of adipokines. Unexpectedly, the phenotypes and metabolic parameters of the mutant mice, which showed early postnatal mortality, are uniquely distinct from previously characterized lipodystrophic mouse models.

Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue

“…Moreover, Sirt1 inhibited ATF4 and eliminated ER stress-induced apoptosis in brown adipocytes. Our results notably revealed the relationships between Sirt1, ER stress and mitochondrial apoptosis in brown adipose tissue, although the interaction between ER and mitochondria has been studied in brown adipose tissue [32, 33]. Moreover, Sirt1 is a crucial regulator of TGF-beta/Smad3 signal [34].…”

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

“…Mitochondria-associated GRP78 can bind to RAF1 and this interaction is involved in the maintenance of mitochondrial permeability and thus protective against ER-stress-induced apoptosis 64 . In support of the anti-apoptotic functions of GRP78, knockout of Grp78 in various tissues led to caspase activation and tissue atrophy 33,34,65,66 (Supplemental Table 2). In breast, prostate and leukemic cancer models, heterozygous and/or homozygous knockout of Grp78 increased tumour apoptosis and impeded tumour progression 39,47,48 (Table 1).…”

Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis

“…Knockdown of GRP78 significantly delayed adipocyte differentiation from MEFs or preadipocytes (Zhu et al, ). In contrast, Grp94‐/‐ ESCs are capable of differentiating into adipocytes (Mao et al, ).…”