The superoxide dismutase mimetic manganese [III] tetrakis [5,10,15,20]-benzoic acid porphyrin (MnTBAP) is a potent antioxidant compound that has been shown to limit weight gain during short-term high fat feeding without preventing insulin resistance. However, whether MnTBAP has therapeutic potential to treat pre-existing obesity and insulin resistance remains unknown. To investigate this, mice were treated with MnTBAP or vehicle during the last five weeks of a 24-week high fat diet (HFD) regimen. MnTBAP treatment significantly decreased body weight and reduced white adipose tissue (WAT) mass in mice fed a HFD and a low fat diet (LFD). The reduction in adiposity was associated with decreased caloric intake without significantly altering energy expenditure, indicating that MnTBAP decreases adiposity in part by modulating energy balance. MnTBAP treatment also improved insulin action in HFD-fed mice, a physiologic response that was associated with increased protein kinase B (PKB) phosphorylation and expression in muscle and WAT. Since MnTBAP is a metalloporphyrin molecule, we hypothesized that its ability to promote weight loss and improve insulin sensitivity was regulated by heme oxygenase-1 (HO-1), in a similar fashion as cobalt protoporphyrins. Despite MnTBAP treatment increasing HO-1 expression, administration of the potent HO-1 inhibitor tin mesoporphyrin (SnMP) did not block the ability of MnTBAP to alter caloric intake, adiposity, or insulin action, suggesting that MnTBAP influences these metabolic processes independent of HO-1. These data demonstrate that MnTBAP can ameliorate pre-existing obesity and improve insulin action by reducing caloric intake and increasing PKB phosphorylation and expression.

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The present study determined if carbon monoxide (CO) treatment reversed diet-induced obesity and insulin resistance. Because CO is a potential ligand for the nuclear receptor Rev-erb-α, we also determined if CO treatment altered the mRNA expression of Rev-erb-α targets. Mice were fed a low fat diet (LFD) or a high fat diet (HFD) for 150 days. Following 110 days of the dietary intervention the HFD-fed mice were assigned to a CO inhalation group or a control group. The HFD-CO group was exposed to 250 ppm CO for one hour per day for 40 consecutive days. Body weight and edpididymal white adipose tissue (EWAT) mass were significantly elevated in HFD and HFD-CO mice compared to LFD mice, but no differences existed between HFD and HFD-CO mice. Area under the insulin-assisted glucose tolerance curve was significantly elevated in HFD and HFD-CO mice compared to LFD mice, but no differences existed between HFD and HFD-CO mice. Heme oxygenase-1 (HO-1) mRNA was significantly higher in EWAT of HFD-CO compared to HFD mice, indicating effective delivery of CO to adipose tissue. CO treatment did not alter Rev-erb-α expression or Rev-erb-α targets. These results indicate that CO inhalation does not attenuate diet-induced obesity/insulin resistance.