leptin and sulforaphane

The ascending prevalence of obesity in recent decades is commonly associated with soaring morbidity and mortality rates, resulting in increased health-care costs and decreased quality of life. A systemic state of stress characterized by low-grade inflammation and pathological formation of reactive oxygen species (ROS) usually manifests in obesity. The transcription factor nuclear factor erythroid-derived 2-like 2 (NRF2) is the master regulator of the redox homeostasis and plays a critical role in the resolution of inflammation. Here, we show that the natural isothiocyanate and potent NRF2 activator sulforaphane reverses diet-induced obesity through a predominantly, but not exclusively, NRF2-dependent mechanism that requires a functional leptin receptor signaling and hyperleptinemia. Sulforaphane does not reduce the body weight or food intake of lean mice but induces an anorectic response when coadministered with exogenous leptin. Leptin-deficient

Topics: Animals; Inflammation; Isothiocyanates; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Quality of Life; Reactive Oxygen Species; Receptors, Leptin; Sulfoxides

Nonalcoholic fatty liver disease (NAFLD) is a major health concern. Endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may be targeted to prevent the progress of nonalcoholic fatty liver disease. Sulforaphane (SFN), a sulfur-containing compound that is abundant in broccoli florets, seeds, and sprouts, has been reported to have beneficial effects on attenuating metabolic diseases. In light of this, the present study was designed to elucidate the mechanisms by which SFN ameliorated ER stress, inflammation, lipid metabolism, and insulin resistance - induced by a high-fat diet and ionizing radiation (IR) in rats. In our study, the rats were randomly divided into five groups: control, HFD, HFD + SFN, HFD + IR, and HFD + IR + SFN groups. After the last administration of SFN, liver and blood samples were taken. As a result, the lipid profile, liver enzymes, glucose, insulin, IL-1β, adipokines (leptin and resistin), and PI3K/AKT protein levels, as well as the mRNA gene expression of ER stress markers (IRE-1, sXBP-1, PERK, ATF4, and CHOP), fatty acid synthase (FAS), peroxisome proliferator-activated receptor-α (PPAR-α). Interestingly, SFN treatment modulated the levels of proinflammatory cytokine including IL-1β, metabolic indices (lipid profile, glucose, insulin, and adipokines), and ER stress markers in HFD and HFD + IR groups. SFN also increases the expression of PPAR-α and AMPK genes in the livers of HFD and HFD + IR groups. Meanwhile, the gene expression of FAS and CHOP was significantly attenuated in the SFN-treated groups. Our results clearly show that SFN inhibits liver toxicity induced by HFD and IR by ameliorating the ER stress events in the liver tissue through the upregulation of AMPK and PPAR-α accompanied by downregulation of FAS and CHOP gene expression.

Topics: AMP-Activated Protein Kinases; Animals; Cytokines; Diet, High-Fat; Endoplasmic Reticulum Stress; Fatty Acid Synthases; Glucose; Insulins; Isothiocyanates; Leptin; Lipids; Liver; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Resistin; RNA, Messenger; Sulfoxides; Up-Regulation

Diet-induced obesity (DIO) is commonly associated with hyperleptinemia and leptin resistance. Leptin acts centrally to inhibit food intake and increase energy expenditure, thereby preventing body weight gain. Resistance to the biological effects of leptin represents a major obstacle in utilizing exogenously administered leptin as a treatment option for obesity. Of importance, recent studies demonstrate that naturally occurring compounds improve leptin sensitivity in DIO mice, as revealed by anorectic and body weight-lowering effects. To date, the role of sulforaphane (SFN, an isothiocyanate derived from cruciferous vegetables) on leptin responsiveness has not been examined, in spite of its known beneficial effects toward lowering body weight gain in DIO. In the present study, we determined the extent to which SFN regulates leptin responsiveness in high-fat high-sucrose (HFHS) diet-fed obese mice. SFN treatment (0.5 mg/kg/day, s.c.) for 23 days in HFHS-fed mice improved the responsiveness to intraperitoneally-injected leptin by promoting significant decreases in cumulative food intake and body weight gain. A single leptin injection (2 mg/kg; i.p.) resulted in significant decreases in food intake at 24 h and 38 h time points. In addition, a triple leptin injection (1 mg/kg/day, 3 days; i.p.) led to significant decreases in food intake at 14 h, 24 h, 38 h, 48 h, and 62 h time points. Furthermore, single and triple leptin injections prevented body weight gain at 38 h and 62 h time points, respectively. The present findings suggest that intervention with SFN, a naturally occurring isothiocyanate, has the potential to improve leptin responsiveness in DIO.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Isothiocyanates; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Sucrose; Sulfoxides

Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Obesity Agents; Anticarcinogenic Agents; Antioxidants; Aorta; Cell Proliferation; Cells, Cultured; Diet, Western; Femoral Artery; Humans; Injections, Subcutaneous; Insulin Resistance; Isothiocyanates; Leptin; Male; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Neointima; Obesity; Oxidative Stress; Sulfoxides; Weight Gain