TRPV1 Activation by Capsaicin Mediates Glucose Oxidation and ATP Production Independent of Insulin Signalling in Mouse Skeletal Muscle Cells

Abstract

Background: Insulin resistance (IR), a key characteristic of type 2 diabetes (T2DM), is manifested by decreased insulin-stimulated glucose transport in target tissues. Emerging research has highlighted transient receptor potential cation channel subfamily V member (TRPV1) activation by capsaicin as a potential therapeutic target for these conditions. However, there are limited data on the effects of capsaicin on cell signalling molecules involved in glucose uptake. Methods: C2C12 cells were cultured and differentiated to acquire the myotube phenotype. The activation status of signalling molecules involved in glucose metabolism, including 5’ adenosine monophosphate-activated protein kinase (AMPK), calcium/calmodulin-dependent protein kinase 2 (CAMKK2), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), protein kinase B (AKT), and src homology phosphatase 2 (SHP2), was examined. Finally, activation of CAMKK2 and AMPK, and glucose oxidation and ATP levels were measured in capsaicin-treated cells in the presence or absence of TRPV1 antagonist (SB-452533). Results: Capsaicin activated cell signalling molecules including CAMKK2 and AMPK leading to increased glucose oxidation and ATP generation independent of insulin in the differentiated C2C12 cells. Pharmacological inhibition of TRPV1 diminished the activation of CAMKK2 and AMPK as well as glucose oxidation and ATP production. Moreover, we observed an inhibitory effect of capsaicin in the phosphorylation of ERK1/2 in the mouse myotubes. Conclusion: Our data show that capsaicin-mediated stimulation of TRPV1 in differentiated C2C12 cells leads to activation of CAMKK2 and AMPK, and increased glucose oxidation which is concomitant with an elevation in intracellular ATP level. Further studies of the effect of TRPV1 channel activation by capsaicin on glucose metabolism could provide novel therapeutic utility for the management of IR and T2DM.

Capsaicin and Zinc Promote Glucose Uptake in C2C12 Skeletal Muscle Cells through a Common Calcium Signalling Pathway

“…Capsaicin acts through the activation of TRPV1, a calcium-permeable ion channel [1,44,45]. Many in vitro, animal, and human studies have confirmed the beneficial role of capsaicin in the modulation of glucose metabolism [1,3,7,12,19,46]. Similarly, zinc affects glucose homeostasis through various pathways, activating signalling molecules involved in glucose uptake and insulin action such as protein kinase B (AKT), small heterodimer partner (SHP), and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), in both healthy and diabetic individuals [2,4,5,8,15].…”

“…Emerging studies on the importance of food components on glucose metabolism have highlighted capsaicin and zinc as potential therapeutic targets for carbohydrate metabolism diseases [1][2][3][4]. Capsaicin, the bioactive phenolic component of chilli peppers, has potential benefits in the reduction of glucose metabolism disorders and acts through the activation of transient receptor potential cation channel subfamily V member (TRPV1) [1,3]. Similarly, zinc plays an essential role in the prevention of carbohydrate metabolism diseases, and disruption in zinc homeostasis is strongly associated with the pathogenesis of these disorders [2,5].…”

“…Although extensive research demonstrates the beneficial effects of capsaicin and zinc on glucose homeostasis [1,7,9,17,18], there is limited information to describe the mechanism of action of these two food components in skeletal muscle glucose metabolism [2,3,19]. Capsaicin influences glucose metabolism independent of insulin signal transduction in mouse skeletal muscle cells [3,19]. Like capsaicin, the advantageous effects of zinc on glucose homeostasis are well-established in the literature [20,21].…”

“…Zinc stimulates glucose uptake through the activation of insulin signalling molecules in mouse skeletal muscle cells [2,22]. Based on our previous work, the central signalling pathways activated by capsaicin and zinc are distinct [2,3,22]; however, it appears that calcium signalling cascade is the common pathway between capsaicin and zinc in skeletal muscle cells [23,24]. Understanding the joint signalling pathway activated by capsaicin and zinc could potentially lead to the development of a combination therapy that is more efficient for the treatment of carbohydrate metabolism disorders.…”

“…While several studies partly described the molecular signals activated by capsaicin and zinc in glucose metabolism, the effect of calcium signal transduction on glucose uptake by these two bioactive food components is not fully investigated in skeletal muscle cells [1][2][3]19,22].…”