Isodihydrocapsiate stimulates plasma glucose uptake by activation of AMP-activated protein kinase

https://doi.org/10.1016/j.bbrc.2008.04.061Get rights and content

Abstract

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is implicated as a key factor in controlling whole body homeostasis, including fatty acid oxidation and glucose uptake. We report that a synthetic structural isomer of dihydrocapsiate, isodihydrocapsiate (8-methylnonanoic acid 3-hydroxy-4-methoxy benzyl ester) improves type 2 diabetes by activating AMPK through the LKB1 pathway. In L6 myotube cells, phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and glucose uptake were significantly increased, whereas these effects were attenuated by an AMPK inhibitor, compound C. In addition, increased phosphorylation of AMPK and ACC by isodihydrocapsiate was significantly reduced by radicicol, an LKB1 destabilizer, suggesting that increased glucose uptake in L6 cells with isodihydrocapsiate treatment is predominantly accomplished by a LKB1-mediated AMPK activation pathway. Oral administration of isodihydrocapsiate to diabetic (db/db) mice reduced blood glucose levels by 40% after a 4-week treatment period. Our results support the development of isodihydrocapsiate as a potential therapeutic agent to target AMPK in type 2 diabetes.

Section snippets

Material and methods

Chemicals and reagents. L6 skeletal muscle cells were obtained from the American Type Culture Collection (Manassas, VA, USA). Fetal bovine serum (FBS), minimum essential medium α (α-MEM), trypsin/EDTA, and penicillin/streptomycin were obtained from Invitrogen (Carlsbad, CA, USA). Compound C and radicicol were purchased from Calbiochem (Merck, Darmstadt, Germany). The 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), BSA, and other chemicals were obtained from Sigma Chemical Co. (St.

Results

To investigate whether or not capsaicinoid-like substances mediate the AMPK signaling cascade, isodihydrocapsiate (Fig. 1), a structural isomer of dihydrocapsiate [22] was synthesized and then tested for its ability to activate AMPK. As shown in Fig. 2A, we found that treatment of L6 myotube cells with 100 μM isodihydrocapsiate increased phosphorylation of the Thr-172 residue of the AMPK α subunit and the Ser-79 subunit of ACC in a time-dependent manner without changing the total protein levels

Discussion

Capsiate [4-hydroxy-3-methoxybenzyl (E)-8methyl-6-nonoenoate] and dihydrocapsiate are the ester analogues of capsaicin, and, recently, these two capsaicinoid-like substances were either purified from the fruits of the non-pungent sweet pepper (CH-19 Sweet) or chemically synthesized [22], [27]. Recent reports also indicate that capsaicinoid-like substances share some of capsaicin’s physiological activities, such as the elevation of body temperature, the stimulation of energy expenditure, and the

Acknowledgments

This work was supported by a Grant (PF06212-00) from the Plant Diversity Research Center of the 21st Century Frontier Research Program, which is funded by the Ministry of Science and Technology of the Korean government.

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