The possible potentiating role of endoplasmic reticulum stress response inhibitors in trans-differentiation of white to brown adipocytes

Abstract

The brown adipose tissue (BAT) is an organ with the specialised function of intracellular fat oxidation; in other words, brown fat points to a potential natural tool by which energy expenditure is being stimulated. Obesity is a serious illness which can lead to many medical complications such as cardiovascular disorders. The BAT production, therefore, could be a promising therapeutic strategy for managing obesity. While different approaches have been examined to generate brown adipocytes from various precursor cells, no study has proposed an efficient procedure for direct trans-differentiation of white to brown adipocytes. Bone morphogenic protein (BMP)-7 is a possible potential agent by which most of the main factors involved in induction of brown adipocytogenesis such as early regulators of brown fat fate, positive regulatory domain containing 16 (PRDM16) and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1 alpha (PGC-1α) are stimulated, but the rate of success was not so promising. It has been documented that mature white adipocytes exert endoplasmic reticulum stress response (ESR) and consequently unfolded protein response (UPR) becomes activated for the purpose of ESR recovery since the ESR exceeds the capacity of UPR to overcome the imposed stress, and in turn disables the cell to manage the protein synthesis cascade including those required for BMP-7 induction of brown adipogenesis. This was performed using three main ESR sensors: PKR-like endoplasmic reticulum kinase (PERK), inositol requiring enzyme-1 (IRE-1) and activating transcription factor 6 alpha (ATF-6α) resulting in attenuation of protein translation by blocking the activation of transcriptional machinery of UPR genes and the cell behaviour would also be changed towards apoptosis.

It may suggest and propose the hypothesis that pretreatment of the white adipocyte with an ESR inhibitor such as salubrinal by reducing ESR and turning on the protein synthesis machinery required for BMP-7 induction of brown adipogenesis cascade could provide a more efficient and successful method of transdifferentiation procedure of white to brown adipocytes.