Metabolic syndrome is a cluster of conditions—increased blood pressure, a high blood sugar level, abdominal fat accumulation and abnormal cholesterol levels—that occur together, increasing the risk of heart disease, stroke and type 2 diabetes mellitus (T2DM). Mitochondria play a central role in the energy metabolism. Mitochondrial dysfunction contributes to the pathogenesis of metabolic disorders. Abnormality in mitochondrial function is a leading cause for development of insulin resistance and is promoted, at least partly, through lipid accumulation in ectopic tissues, including liver and skeletal muscle. Many growth and transcription factors involved in the regulation of mitochondrial gene expression also contribute to the pathophysiology of obesity, insulin resistance and type-2 diabetes. The role of mitochondria as functional organelles, and the signaling molecules produced by them are critical in the regulation of cellular energy metabolism and homeostasis. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) encoding a 16-amino-acid peptide is a recently identified peptide. The skeletal muscle appears to be the main target organ for MOTS-c and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c increases glucose utilization, promotes insulin sensitivity and metabolic homeostasis through activation of AMPK dependent mechanisms in skeletal muscle. In rodent studies MOTS-c has been demonstrated to protect against insulin resistance induced by diet and ageing. However the role of MOTS-c in adipocytes is largely unknown. In this current study we aimed to study the effect of MOTS-c on adipocyte development and metabolism in cultured mouse adipocytes.


3T3L1 cells were grown in DMEM media containing 10% FBS. Cells were stimulated with various concentrations of MOTS-c (100 nM to 50 μM) to study the effect of MOTS-c on cell viability. For differentiation pre-adipocytes were grown in differentiation induction medium containing dexamethasone, IBMX and insulin for two days. The media was replaced with medium containing insulin only for the next six days. About 60–70% differentiation was achieved by day 8. For treatment group pre-adipocytes were pre-treated with MOTS-c for 24 hours, and then differentiated into adipocytes for eight days. Quantitative real-time PCR was used to investigate the effect of MOTS-c on adipogenic genes expression:, Peroxisome Proliferator-Activated Receptor Gamma (PPARg), AP2, adiponectin and leptin in mouse 3T3-L1 pre-adipocytes.


MOTS-c treatment did not induce any significant changes in cell viability at 24h following treatment. Pretreatment with MOTS-c prior to induction of differentiation down regulated expression of adipogenic markers including leptin, adiponectin, PPARg and PPARg-coactivator 1-alpha (PGC1a) mRNA levels, compared to differentiated adipocyte controls.


Our primary result indicates that MOTS-c inhibits adipogenesis through down-regulation of multiple genes involved in development of adipocytes, and this inhibition could contribute to the reduced abdominal adiposity. Future studies are currently in progress to further assess the effects of MOTS-c on adipocytes lipolysis, glucose uptake, glucose transporter (GLUT) family and other insulin-signaling pathway protein including GSK3B, IGF1R, IGF2R, and PIK3K are needed to understand the role of MOTS-c in mouse 3T3-L1 adipocytes.


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