DHL-HisZn, a novel antioxidant, enhances adipogenic differentiation and antioxidative response in adipose-derived stem cells.
Adipose-derived stem cells (ASCs) are multipotent progenitor cells that have the capacity to differentiate into specific mesenchymal cell lineages including adipocytes in response to environmental cues. Dysfunctional adipose tissue, rather than an excess of adipose tissue, has been proposed as a key factor in the pathogenesis of obesity-related diseases. The insulin-sensitizing effects of antidiabetic drugs are mediated by activation of peroxisome proliferator-activated receptor gamma (PPARγ). Here, we investigated the effects of sodium zinc histidine dithiooctanamide (DHL-HisZn), a strong antioxidant, on PPARγ activation, adipocyte differentiation and insulin sensitivity. Additionally, the effects of DHL-HisZn on cellular antioxidant response and inflammatory cytokine production were also evaluated. In ASCs, DHL-HisZn enhanced adipocyte differentiation and PPARγ expression in a dose-dependent manner. DHL-HisZn also increased the relative abundance of insulin-responsive glucose transporter 4 (GLUT4) and adiponectin mRNA. Furthermore, DHL-HisZn upregulated PPARγ downstream target gene expression. In addition, treatment with DHL-HisZn upregulated mRNA levels of endogenous antioxidants, such as glucose-6-phosphate dehydrogenase (G6PD), superoxide dismutase 2 (SOD2), catalase (CAT) and glutathione reductase (GR). DHL-HisZn treatment enhanced insulin signaling and inhibited NF-κB activation, which subsequently suppressed inflammatory cytokine IL-6 expression. Our results indicate that DHL-HisZn enhances insulin sensitivity in adipocytes by increasing the expression of GLUT4 and IRS-1 via the activation of PPARγ and improving the antioxidant response during adipogenic differentiation. Therefore, DHL-HisZn may have the capability to reduce insulin resistance.
Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Chien-Chih
CC
Chen
Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Li-Wen
LW
Hsu
Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Toshiaki
T
Nakano
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Kuang-Tzu
KT
Huang
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Kuang-Den
KD
Chen
Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan.
Chia-Yun
CY
Lai
Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan; Faculty of Nursing, Josai International University, Chiba Ken 283, Japan. Electronic address: pochigoto0224@gmail.com.
Shigeru
S
Goto
Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung City 833, Taiwan. Electronic address: clchen@adm.cgmh.org.tw.
Chao-Long
CL
Chen
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects* / Q000235:genetics; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006639:Histidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008063:Thioctic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D052242:Adiponectin; D000975:Antioxidants; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D047495:PPAR gamma; D012333:RNA, Messenger; C572452:zinc histidine dithiooctanamide; D006639:Histidine; D008063:Thioctic Acid; D008071:Lipoprotein Lipase
Adipogenic differentiation; Antioxidant; DHL-HisZn; Insulin resistance; PPARγ