trans-Cinnamaldehyde

Cinnamaldehyde is a flavonoid that is naturally synthesized by the shikimate pathway. Its supplementation can improve glucose and lipid homeostasis in diabetic animals; a TRPA1 agonist.

Cinnamaldehyde (40 μM) could enhance the expression of hormone-sensitive lipase (HSL), and suppress the expression of perilipin and glycerol-3-phosphate dehydrogenase as well as reduce adipocyte genes expression of peroxisome proliferator-activated receptor (PPAR)-γ and CCAAT/enhancer-binding protein-α (CEBP-α) in 3T3-L1 pre-adipocytes. It also increases expression of PPARδ and PPARγ as well as its targeted genes such as aP2 and CD36 in 3T3-L1 differentiated adipocytes. Cinnamaldehyde (40 μM) treatment increases GLUT4 expression via activating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and triggering its downstream effector myocyte enhancer factors 2 (MEF2) in C2C12 cells. Its treatment regulates oxidative metabolism through increasing expressions of 5'-adenosine monophosphate-activated protein kinase (AMPK), NAD+-dependent deacetylases sirtuin 1, PGC-1α and cytochrome C as well as improving PPARα and PPARβ/δ expression, which contributes to mitochondrial biogenesis. However, cinnamaldehyde is demonstrated to inhibit mitochondrial metabolism by reducing basal and chemically-induced peak myotube oxidative metabolism in C2C12 cells[1]. Cinnamaldehyde exerts cytotoxic effects on human leukemia K562 cells by inducing apoptosis and synergizing the cytotoxicity of CIK cells against K562 cells[3].

Cinnamaldehyde exhibits glucolipid lowering effects in diabetic animals by increasing glucose uptake and improving insulin sensitivity in adipose and skeletal muscle tissues, improving glycogen synthesis in liver, restoring pancreatic islets dysfunction, slowing gastric emptying rates, and improving diabetic renal and brain disorders. Cinnamaldehyde exerts these effects through its action on multiple signaling pathways, including PPARs, AMPK, PI3K/IRS-1, RBP4-GLUT4, and ERK/JNK/p38MAPK, TRPA1-ghrelin and Nrf2 pathways. In addition, cinnamaldehyde seems to regulate the activities of PTP1B and α-amylase. Oral administration of cinnamaldehyde ranging from 20mg/kg to 40 mg/kg per day for a duration lasting from 21 to 60 days results in a significant improvement in the levels of blood glucose and glycosylated hemoglobin (HbA1C) as well as insulin sensitivity in STZ-induced diabetic rats. Cinnamaldehyde is not stable in the body, with the possibility of metabolizing into cinnamic acid and transforming into cinnamyl alcohol. Excessive doses of cinnamaldehyde may generate the toxic response. In human, 3% cinnamaldehyde may cause skin irritation. Cinnamaldehyde is demonstrated to decrease serum IL-1β and inhibit inflammatory gene expression (COX-2, MCP-1, TNF-α, and IL-6) in WAT of HFD insulted male Swiss albino mice and C57BLKS db/db mice, while increased expression of Cpt1a protects against pro-inflammatory adipokines release and promotes fatty acid oxidation, which contributes to an improvement in insulin resistance[1].

[1] Zhu R, et al. Pharmacol Res. 2017, 122:78-89. [2] Tamura Y, et al. J Nutr Sci Vitaminol (Tokyo). 2012, 58(1):9-13. [3] Zhang JH, et al. Acta Pharmacol Sin. 2010, 31(7):861-6.