Mild Electrical Stimulation Increases Stress Resistance and Suppresses Fat Accumulation via Activation of LKB1-AMPK Signaling Pathway in C. elegans

Abstract

Electrical current at physiological strength has been applied as a therapeutic approach for various diseases. Several of our works showed that mild electrical stimulation (MES) at 0.1-ms pulse width has positive impact on organisms. But despite the growing evidence of the beneficial effects of MES, its effects on individual animals and the molecular underpinnings are poorly understood and rarely studied. Here, we examined the effects of MES on individual animal and its mechanisms by mainly using Caenorhabditis elegans, a powerful genetic model organism. Interestingly, MES increased stress resistance and suppressed excess fat accumulation in wild-type N2 worms but not in AMPK/AAK-2 and LKB1/PAR-4 mutant worms. MES promoted the nuclear localization of transcription factors DAF-16 and SKN-1 and consequently increased the expression of anti-stress genes, whereas MES inhibited the nuclear localization of SBP-1 and suppressed the expression of lipogenic genes. Moreover, we found that MES induced the activation of LKB1/PAR4-AMPK/AAK2 pathway in C. elegans and in several mammalian cell lines. The mitochondrial membrane potential and cellular ATP level were slightly and transiently decreased by MES leading to the activation of LKB1-AMPK signaling pathway. Together, we firstly and genetically demonstrated that MES exerts beneficial effects such as stress resistance and suppression of excess fat accumulation, via activation of LKB1-AMPK signaling pathway.

Mild electrical stimulation with heat shock reduces inflammatory symptoms in the imiquimod‐induced psoriasis mouse model

“…We demonstrated in a previous study that MES+HS treatment ameliorated the sterile inflammation in chronic kidney disease mouse model via activating some signaling pathways . In particular, we confirmed that MES+HS treatment activates AMPK in various types of cells . In imiquimod‐treated skin, MES+HS significantly activated AMPK (Figure A,B).…”

“…The therapeutic effects of combination treatment (MES+HS) are higher than those of MES alone or HS alone. In addition, we showed that MES+HS exerts biological effects via activation of intracellular signaling pathways such as p53 and LKB1‐AMPK axis . In clinical studies for subjects with type 2 diabetes mellitus and metabolic syndrome, MES+HS treatment significantly ameliorated the insulin resistance and inflammatory parameters without any adverse effects .…”

Activation of heat shock response to treat obese subjects with type 2 diabetes: a prospective, frequency-escalating, randomized, open-label, triple-arm trial

“…As AMPK knockdown increased fat mass and exacerbates the inflammatory phenotype 13 , activation of AMPK by MES + HS may reduce visceral adiposity. Indeed, lipid accumulation in C. elegans was attenuated by MES alone through liver kinase B1-AMPK signaling activation 14 . These lines of evidence suggest that HSP72 stimulates fat oxidation, resulting in reduced fat storage and adiposity.…”

“…When MES + HS treatment is performed, cytoplasmic HSP72 levels are increased and act as an inhibitor of JNK and NF-κB signals, resulting in the attenuation of cytokine production, thereby improving insulin resistance. In addition, activation of AMPK by MES 14 may directly activate GLUT4 translocation independent of insulin signaling. To note, the reduction in visceral adiposity is not correlated with the decrease in HbA1c, glucose levels or HOMA-IR, indicating that MES + HS treatment may directly attenuate the inflammatory signaling cascade to improve glucose homeostasis.…”

Transgenerational lipid‐reducing activity of benzylisoquinoline alkaloids in Caenorhabditis elegans

“…Sublethal stress pretreatments in diverse combinations of stressors and recipient organisms have been shown to increase germination in plants, animal cell proliferation in culture, protein turnover, subsequent stress resistance and life span extension. An increased life span has been reported to result from diverse types of stressors, such as heat, cold, oxidative stress, radiation, electrical stimulation, exercise and fasting (Chuang, Kuo, Lee, Chu, & Chen, ; Lagisz, Hector, & Nakagawa, ; Matsuyama et al, ; Rechavi et al, ; Ristow & Schmeisser, ). However, the biological mechanisms of these stress treatment effects are not fully understood.…”