trans-Cinnamaldehyde stimulates mitochondrial biogenesis through PGC-1α and PPARβ/δ leading to enhanced GLUT4 expression

• Published in: Biochimie 2015-12, Vol.119, p.45-51
• Main Authors: Gannon, Nicholas P., Schnuck, Jamie K., Mermier, Christine M., Conn, Carole A., Vaughan, Roger A.
• Format: Article
• Language: English
• Subjects: Acrolein - adverse effects; Acrolein - analogs & derivatives; Acrolein - metabolism; Animals; Biomarkers - metabolism; Cell Line; Cell Survival; Flavoring Agents - adverse effects; Flavoring Agents - metabolism; Gene Expression Regulation; Glucose transporter 4 (GLUT4); Glucose Transporter Type 4 - agonists; Glucose Transporter Type 4 - genetics; Glucose Transporter Type 4 - metabolism; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - metabolism; Lipid Metabolism; MEF2 Transcription Factors - agonists; MEF2 Transcription Factors - genetics; MEF2 Transcription Factors - metabolism; Mice; Mitochondria, Muscle - enzymology; Mitochondria, Muscle - metabolism; Mitochondrial biogenesis; Mitochondrial Dynamics; Muscle Fibers, Skeletal - enzymology; Muscle Fibers, Skeletal - metabolism; Organelle Biogenesis; Oxidation-Reduction; Oxidative metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - agonists; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α); PPAR delta - agonists; PPAR delta - metabolism; PPAR-beta - agonists; PPAR-beta - metabolism; Type II diabetes mellitus
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2015.10.001

Type 2 diabetes is characterized by insulin resistance and chronic hyperglycemia, and is increasing in incidence and severity. This work explored the effects of trans-cinnamaldehyde (CA) on carbohydrate metabolism, mitochondrial content, and related metabolic gene and protein expression in cultured myotubes treated with various concentrations of CA for up to 24 h. CA treatment increased myotube myocyte enhancer factor 2 (MEF2) along with glucose transporter 4 (GLUT4) content. CA treatment also significantly increased expression of markers of improved oxidative metabolism including 5′ adenosine monophosphate-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), cytochrome c (CytC), as well as peroxisome proliferator-activated receptor α (PPARα) and PPARβ/δ. Despite increased expression of proteins associated with improved oxidative metabolism and glucose uptake, CA-treated myotubes exhibited significantly reduced oxidative metabolism compared with controlled cells. Additionally, CA treatment increased markers of glucose-mediated lipid biosynthesis without elevated PPARγ and sterol receptor element binding protein 1c (SREBP-1c) expression. The ability of CA to stimulate mitochondrial biogenesis and GLUT4 expression suggests CA may offer possible benefits for metabolic disease. However, increases in markers of fatty acid synthesis with simultaneously reduced oxidative metabolism suggest CA may have counterproductive effects for metabolic disease, warranting a need for further investigation. Working hypotheses of CA mechanism of myotube PGC-1α induction leading to increased GLUT4 content. Under conditions of normal glucose content, (1) CA enters the cell and inhibits mitochondrial oxidative metabolism (through an unknown mechanism) leading to decreased ATP content. Reduced ATP content stimulates AMPK (2) leading to the activation and phosphorylation of PGC-1α and other downstream targets including PPARα and PPARβ/δ, promoting PGC-1α, PPAR, and SIRT1 expression (3). Increased PGC-1α expression leads to heightened MEF2 expression (4) and ultimately increased GLUT4 content (5). Increased PGC-1α expression also stimulates mitochondrial biogenesis (6). Increased PPARβ/δ activation leads to heightened expression of SIRT1 leading to enhanced PGC-1α activation (7). And (8), increased GLUT4 content may ultimately increase glucose uptake stabilizing cellular ATP content/energetics (although these hypotheses require furth