Relationship between the Acyl Chain Length of Paradol Analogues and Their Antiobesity Activity following Oral Ingestion

Abstract

6-Paradol is known to activate thermogenesis in brown adipose tissue (BAT), and paradol analogues with different acyl chain lengths possess different pungency thresholds. In this study, the influence of the acyl chain length on the antiobesity activity of the paradol analogues was investigated. The antiobesity activity of 6-paradol in mice fed a high-fat diet for 8 weeks was greater than that of dihydrocapsiate. A comparison of the antiobesity activities of zingerone and 6-paradol showed that the length of the acyl chain in the paradol analogue was important for strong activity. Furthermore, the antiobesity activities of 6-, 8-, and 12-paradol appeared to decrease in an acyl chain length-dependent manner. The mechanism of the antiobesity activity of 6-paradol was enhanced by increasing levels of energy metabolism in the BAT, as well as an increase in the expression of uncoupling proteins 1 via the activation of sympathetic nerve activity.

Neuroprotective Effect of 6-Paradol in Focal Cerebral Ischemia Involves the Attenuation of Neuroinflammatory Responses in Activated Microglia

“…In this study, it appears that 6-paradol is the most effective one among the tested paradol derivatives in reducing inflammatory responses in activated microglia. In fact, our notion can be further supported by several reports where 6-paradol is the most effective compound for modulating obesity, platelet aggregation, or 12- O -tetradecanoylphorbol-13-acetate-induced alterations when compared to other paradol derivatives [ 19 , 29 , 34 ].…”

“…They are also found in nature and thought to be biological metabolites of shogaols. Recently, there have been a few reports where the chain lengths of shogaols or paradols affect their pharmacokinetics and biological activities, such as neuronal protection from β-amyloid formation and antiobesity activity [ 29 , 30 , 31 ]. One study reported that shogaols with longer chain (4- to 12-shogarol) had better neuroprotection [ 30 ].…”

6-Paradol and 6-Shogaol, the Pungent Compounds of Ginger, Promote Glucose Utilization in Adipocytes and Myotubes, and 6-Paradol Reduces Blood Glucose in High-Fat Diet-Fed Mice

“…Our data showed that zingerone demonstrated an insignificant effect compared to those of other derivatives. The importance of the alkyl chain length on bioactivity was also reported in previous studies focusing on the antioxidant activity of ginger secondary metabolites and the anti-obesity activity of paradol analogues [ 33 , 38 ].…”

“…Among the tested compounds, shogaols and paradols exhibited better activity and therefore were considered for further experimentation. However, insignificant glucose uptake activity of 10-paradol, along with the previously-reported data showing poor bioavailability of 8-paradol [ 33 ], motivated us to select 6-paradol and 6-, 8- and 10-shogaols for further investigation. 6-Paradol and 6-, 8- and 10-shogaols were tested for possible cytotoxic effects in concentration range of 50–400 μM showing that these compounds exerted no toxicity on 3T3-L1 adipocytes up to 200 μM and on C2C12 myotubes up to 100 μM ( Figure 1 C).…”

Small molecules for fat combustion: targeting obesity

“…However, it needs further investigation to fully elucidate the thermogenic effect of miglitol. Another study showed paradol analogues increased energy metabolism in the BAT via the activation of sympathetic nerve activity; and the length of the acyl chain of the paradol analogues had a significant impact on the extent of UCP1 expression level 123 . Using a transgenic animal model expressing luciferase to mimics endogenous UCP1 expression, a potential modulator WWL113 was discovered with capacity to increase UCP1 expression and thermogenic response without significant change in locomotor activity, food intake, or heartbeat 124 .…”