Manganese [III] Tetrakis [5,10,15,20]-Benzoic Acid Porphyrin Reduces Adiposity and Improves Insulin Action in Mice with Pre-Existing Obesity.

Jonathan R Brestoff,Elena Stansky,Aaron Sheppard,Tim Brodsky,Maria Disanto-Rose,Alexandra Z Sosinsky,Ryan Mcloughlin,Leila Fussell,Thomas H Reynolds,Erin E Kershaw,Zane Andrews

doi:10.1371/journal.pone.0137388

Abstract

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.

Highlights

Obesity is an increasingly prevalent metabolic disease [1] that is associated with increased risk of developing type 2 diabetes, a disease that affects approximately 24 million Americans [2] and costs an estimated $245 billion in total health care costs in the United States [3]
MnTBAP treatment was not associated with increased energy expenditure, we found that MnTBAP increased expression of the antioxidant-responsive gene heme oxygenase-1 (HO-1) in adipose tissue (Fig 7), which has been previously been shown to limit obesity and insulin resistance [16,19,21]
The MnTBAP-induced improvements in insulin action is likely partially explained by the substantial reduction in adiposity observed following MnTBAP treatment. It is well-established that weight loss produced by decreasing caloric intake improves insulin action, and we demonstrate that MnTBAP treatment reduced caloric intake and improved insulin action in mice fed a high fat diet (HFD) but not in mice fed a low fat diet (LFD)

Summary

Introduction

Obesity is an increasingly prevalent metabolic disease [1] that is associated with increased risk of developing type 2 diabetes, a disease that affects approximately 24 million Americans [2] and costs an estimated $245 billion in total health care costs in the United States [3]. Oxidative stress and production of reactive oxygen species (ROS) have been linked to the development of insulin resistance and type 2 diabetes [4], suggesting a potential role for ROS in the pathogenesis of these disorders In support of this notion, augmenting the antioxidant defense system in mice improves insulin action in the setting of obesity [5,6,7,8]. A large observational study of older adults demonstrated that higher total dietary antioxidant capacity was associated with improved oral glucose tolerance and insulin action [9] Despite these associations, it remains unclear whether antioxidant supplementation or augmentation of the antioxidant defense system is therapeutically beneficial in the treatment of established metabolic disease [10,11]. In addition to the lack of consensus on the effect MnTBAP on insulin action, it remains unclear whether MnTBAP reduces adiposity in mice with preexisting obesity

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