Heme Oxygenase‐1 Inhibition Does Not Prevent MnTBAP's Ability to Reduce Adiposity and Increase Insulin Action

Abstract

Metalloporphryins have been shown to cause weight loss by a heme oxygenase‐1 (HO‐1) dependent mechanism. The purpose of this study was to determine if inhibiting HO‐1 with tin mesoporphyrin (SnMP) prevents the reduction in adiposity and the improvement in insulin sensitivity due to manganese tetrakis benzoic acid porphyrin (MnTBAP) treatment. Mice were fed a low fat diet (LFD) or a high fat (HFD) for four months. During the last 30 days of the dietary intervention, mice were given intraperitoneal injections of MnTBAP (10 mg/kg/day), MnTBAP+SnMP (20 mg/kg/day), or vehicle. SnMP treatment did not prevent the ability of MnTBAP to significantly decrease body weight (Vehicle: 42.5±1.8 vs. MnTBAP: 36.7±1.4 vs. MnTBAP+SnMP: 35.8±1.0) or epididymal white adipose tissue (EWAT) weight (Vehicle: 2.52±0.10 vs. MnTBAP: 1.88±0.14 vs. MnTBAP+SnMP: 1.66±0.11). Insulin sensitivity was significantly higher in HFD mice treated with MnTBAP or MnTBAP+SnMP when compared to vehicle treated HFD mice. Since carbon monoxide (CO) is a product of the HO‐1 reaction, it may mediate the anti‐obesity effects of metalloporphyrins. However, treating HFD mice with CO (250 ppm, 1 hr/day, 4 weeks) did not result in a reduction in body weight or EWAT weight, and did not improve insulin sensitivity. These results indicate that the ability of MnTBAP to promote weight loss and improve insulin sensitivity is independent of HO‐1 activity.