Biotin inhibits autophagy to uncouple adipocyte protein synthesis via differential regulation of mtorc1 and endoplasmic reticulum stress signaling

Abstract

Adipogenesis enables organisms to survive under nutrient stress by predominant synthesis and storage of lipids. Biotin determines cellular lipid synthesis by regulating acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acids biosynthesis. Biotin deficiency mimics insulin resistance with attenuation of insulin induced adipogenesis. Additionally, the newlineregulation of tricarboxylic acid cycle (TCA) anaplerosis by biotin establishes metabolic crossroads to demonstrate the interconversion between carbohydrates, lipids and amino acids. For example, the amino acids augment gluconeogenesis and lipogenesis by replenishing TCA cycle intermediates via pyruvate carboxylase, and#946;-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase. Likewise, pyruvate carboxylase also minimizes amino acid anaplerosis by utilizing pyruvate from glucose metabolism and increases the incorporation of amino acids into proteins of various organs. Nevertheless, the evolution of adipocyte specific lipogenic phenotype by biotin questions its role in protein synthesis. The intracellular levels of amino acids are sensed by general control nonderepressible 2 (GCN2) and mechanistic targets of rapamycin complex I (mTORC1) to determine protein synthesis. The interaction of GCN2 with uncharged tRNA under amino acids deprivation inhibits protein synthesis by phosphorylating eukaryotic initiation factor 2and#945; (eIF2and#945;). In contrast, amino acids activate mTORC1 at the lysosomal surface to phosphorylate eukaryotic initiation factor 4E Binding Protein 1 (4E-BP1) and ribosomal p70S6 Kinase (p70S6K) to induce protein synthesis. Furthermore, like biotin, mTORC1 sensitizes insulin signaling and demonstrates tissue specific metabolic phenotype by coordinating carbohydrate, lipid and protein synthesis newline newline