3-Amino-1,2,4-Triazole Induces Quick and Strong Fat Loss in Mice with High Fat-Induced Metabolic Syndrome

Figure 7

Proposed mechanism by which ATZ acts: in the context of HFD-induced obesity and metabolic syndrome in mice (HFD-model), ATZ treatment probably induces heme synthesis inhibition/decrease (1), which blocks adipogenesis by increasing RevErbα gene expression and, possibly, decreasing RevErbα activity (2), leading to apoptosis of adipocytes, evidenced by the increases in mRNA for caspase 1 and cell death activator (CIDEA) (3). This condition promotes inflammatory cell infiltration in epididymal white adipose tissue (eWAT), confirmed by the increased expression of marker genes: cluster of differentiation 68 (CD68), monocyte chemoattractant protein 1 (MCP1 or CCL2), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), and interleukin 18 (IL-18) (4), inducing atrophy in eWAT, as well as the decreases in adipocyte diameter and WAT index (5). As a consequence of fat loss, ATZ elicits a beneficial systemic antiobesity effect and improves the metabolic status by increasing lipolysis in vivo, peroxisome proliferator-activated receptor gamma (PPARγ), glucose transporter 4 (GLUT4), and hormone-sensitive lipase (HSL) genes, as well as by decreasing lipid peroxidation (TBARS), catalase activity, and mRNA for leptin, adiponectin, and beta-3 adrenergic receptor (Adr-β3 receptor) in eWAT. In addition, systemically, ATZ decreases insulin, leptin, nonesterified fatty acid (NEFA), triglyceride (TG) levels, and blood pressure, which results in the improvement of glucose tolerance and insulin sensitivity (6).