**1. Introduction**

Obesity and ectopic lipid accumulation are key contributing hallmarks of metabolic dysfunction, which is the cornerstone of pathogenesis for most comorbidities [1–3]. People with a BMI greater than 30 (>30) have an increased risk for obesity-associated comorbidities that include cardiovascular disease, hypertension, insulin-resistant diabetes, dyslipidemia, and certain cancers [4–7]. Alterations in lipid metabolism also contribute to ectopic lipid accumulation, exacerbating metabolic disorders, especially when combined with limited physical activity. Understanding and combating metabolic dysfunction is essential for improving clinical outcomes and quality of life.

Obesity treatment has been challenging, and exercise continues to be the foundation for obesity prevention and treatment. Despite the continued interest in exercise training in

**Citation:** Thomas, D.T.; DelCimmuto, N.R.; Flack, K.D.; Stec, D.E.; Hinds, T.D., Jr. Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin. *Antioxidants* **2022**, *11*, 179. https://doi.org/10.3390/ antiox11020179

Academic Editors: Elias Lianos and Maria G. Detsika

Received: 9 December 2021 Accepted: 14 January 2022 Published: 18 January 2022

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obesity, there are still challenges, including patients falling short on meeting exercise recommendations over time and limited effectiveness of exercise as a sole driver for stimulating weight loss [8–10].

A common theme found in the literature on the healthy athletic population is how different nutrients, hormones, dietary supplements, and other forms of ergogenic aids [referred to herein as "exercise enhancers" (EEs)] can improve exercise training outcomes to enhance athletic performance. There is also emerging evidence that EEs may augment the metabolic benefits of exercise and, in some cases, modulate inflammation. This review provides a brief overview of exercise in preventing metabolic dysfunction along with the potential role of select antioxidants (i.e., bilirubin and others), vitamin D, and nitrates on improving metabolic outcomes associated with exercise. The primary focus will then shift to describing bilirubin's emerging significance as a potential EE due to its role as a strong antioxidant and metabolic hormone.

This review describes how exercise interacts with bilirubin to further sensitize these newly defined antioxidant and protective metabolic functions as a hormone. The role of exercise and its influence on bilirubin catabolism will be discussed along with proposed theories on how bilirubin may influence physiological adaptations associated with exercise training and how this might impact inflammatory responses. A primary mechanism discussed postulates that as exercise increases reactive oxygen species (ROS) production, increased heme oxygenase (HO-1) activity raises plasma bilirubin levels, which can also directly bind and activate PPARα (peroxisome proliferator-activated receptor α) in metabolic tissues (e.g., adipose, liver, and muscle), which might explain some of the therapeutic benefits observed with exercise (Figure 1). Other important mediators such as HO-1 and PPARs and their impact on exercise and inflammation will be discussed.

**Figure 1.** Overview of heme oxygenase and bilirubin interaction with exercise. Exercise increases reactive oxygen species (ROS) and potentiates oxidative DNA damage. The body compensates with oxidative stress by upregulating heme oxygenase-1 (HO-1), which generates the antioxidant bilirubin to help prevent excessive oxidative damage. Bilirubin also directly binds to the PPARα nuclear receptor to induce genes that suppress lipid accumulation and has cardiogenic and hepato-protective effects.
