The Alkamide trans-Pellitorine Targets PPARγ via TRPV1 and TRPA1 to Reduce Lipid Accumulation in Developing 3T3-L1 Adipocytes

Abstract

Adipose tissue is an important endocrine organ in the human body. However, pathological overgrowth is associated with chronic illness. Regulation of adipogenesis and maturation of adipocytes via bioactive compounds in our daily diet has been in focus of research in the past years and showed promising results for agonists of the ion channels transient receptor potential channel (TRP) V1 and A1. Here, we investigated the anti-adipogenic potential and underlying mechanisms of the alkamide trans-pellitorine present in Piper nigrum via TRPV1 and TRPA1 in 3T3-L1 cells. trans-pellitorine was found to suppress mean lipid accumulation, when applied during differentiation and maturation, but also during maturation phase solely of 3T3-L1 cells in a concentration range between 1 nM and 1 μM by up to 8.84 ± 4.97 or 7.49 ± 5.08%, respectively. Blockage of TRPV1 using the specific inhibitor trans-tert-butyl-cyclohexanol demonstrated that the anti-adipogenic activity of trans-pellitorine depends on TRPV1. In addition, blockage of the TRPA1 channel using the antagonist AP-18 showed a TRPA1-dependent signaling in the early to intermediate stages of adipogenesis. On a mechanistic level, treatment with trans-pellitorine during adipogenesis led to reduced PPARγ expression on gene and protein level via activation of TRPV1 and TRPA1, and increased expression of the microRNA mmu-let-7b, which has been associated with reduced PPARγ levels. In addition, cells treated with trans-pellitorine showed decreased expression of the gene encoding for fatty acid synthase, increased expression of microRNA-103 and a decreased short-term fatty acid uptake on the functional level. In summary, these data point to an involvement of the TRPV1 and TRPA1 cation channels in the anti-adipogenic activity of trans-pellitorine via microRNA-let7b and PPARγ. Since trans-pellitorine does not directly activate TRPV1 or TRPA1, an indirect modulation of the channel activity is assumed and warrants further investigation.

TRPA1 and TRPV1 channels participate in atmospheric-pressure plasma-induced [Ca2+]i response

“…Consistently with several reports showing that 3T3L1 fibroblasts endogenously express multiple TRP channel family members including TRPA1 and TRPV1 23,24 , we observed that 3T3L1 fibroblasts exhibit rises in [Ca 2+ ] i in response not only to APP-HBS exposure but also to either AITC or capsaicin, pharmacological activators of TRPA1 and TRPV1, respectively. Consequently, we confirmed all of these [Ca 2+ ] i responses induced by APP-HBS as well as by these chemical agonists to be significantly suppressed by siRNA-mediated knockdown of TRPA1 and/or TRPV1 (Fig.…”

Role of Thermo-Sensitive Transient Receptor Potential Channels in Brown Adipose Tissue

“…Other Thermo-Sensitive TRP Channels In a pharmacological experiment, TRPA1 was shown expressed in the 3T3-L1 adipocyte cell line, 123) and indirect activation of TRPA1 by trans-pellitorine reduced lipid accumulation. However, functional expression of TRPA1 in adipocytes has not been well established.…”

TRPA1 Agonist Cinnamaldehyde Decreases Adipogenesis in 3T3-L1 Cells More Potently than the Non-agonist Structural Analog Cinnamyl Isobutyrate

“… 26 , 38 However, CAL is also known as a potent agonist of TRPA1 channels, constituting nonselective thermosensitive cation channels, that have been identified in a variety of neuronal and nonneuronal cell types. 25 − 27 Multiple TRPA1-dependent actions for CAL have been reported over the last decades, such as immunomodulatory 39 and vasodilatory 40 actions as well as the secretion of hormones such as serotonin, 27 ghrelin, 12 and PYY. 41 Additionally, the role of TRP channels in the physiological processes of adipogenesis has grown as a topic of extensive research.…”