*Review* **Reactive Oxygen Species (ROS) and Antioxidants as Immunomodulators in Exercise: Implications for Heme Oxygenase and Bilirubin**

**David Travis Thomas 1, Nicholas R. DelCimmuto 2, Kyle D. Flack 3, David E. Stec <sup>4</sup> and Terry D. Hinds, Jr. 5,6,7,\***


**Abstract:** Exercise is commonly prescribed as a lifestyle treatment for chronic metabolic diseases as it functions as an insulin sensitizer, cardio-protectant, and essential lifestyle tool for effective weight maintenance. Exercise boosts the production of reactive oxygen species (ROS) and subsequent transient oxidative damage, which also upregulates counterbalancing endogenous antioxidants to protect from ROS-induced damage and inflammation. Exercise elevates heme oxygenase-1 (HO-1) and biliverdin reductase A (BVRA) expression as built-in protective mechanisms, which produce the most potent antioxidant, bilirubin. Together, these mitigate inflammation and adiposity. Moderately raising plasma bilirubin protects in two ways: (1) via its antioxidant capacity to reduce ROS and inflammation, and (2) its newly defined function as a hormone that activates the nuclear receptor transcription factor PPARα. It is now understood that increasing plasma bilirubin can also drive metabolic adaptions, which improve deleterious outcomes of weight gain and obesity, such as inflammation, type II diabetes, and cardiovascular diseases. The main objective of this review is to describe the function of bilirubin as an antioxidant and metabolic hormone and how the HO-1– BVRA–bilirubin–PPARα axis influences inflammation, metabolic function and interacts with exercise to improve outcomes of weight management.

**Keywords:** HO-1; biliverdin reductase; BVRA; PPARα; bilirubin; inflammation; metabolic disease; nutraceuticals; vitamin D; vitamin E; nitrate
