Obesity has become a global pandemic worldwide over the years (The Lancet Gastroenterology & Hepatology, 2021) with more than 1.9 billion adults being overweight and 650 million were obese (WHO, 2018). Of note, obesity is associated with metabolic syndrome (Marques et al., 2016a) prothrombotic state (Grundy et al., 2004) and increased risk of major adverse cardiovascular events (Khan et al., 2018). In obesity, low-grade inflammation may occur as result of a compromised gut diversity and increased monocyte activation in the adipose tissue through several molecular mechanisms (Jialal et al., 2012). This process induces the polarization of the resident macrophage (M1) cells towards a pro-inflammatory phenotype (Esser et al., 2013). The polarization of macrophages towards M1, is followed by the infiltration of neutrophils influx into the adipose tissue. Neutrophil infiltration is a characteristic features of obesity-induced inflammation that contributes to the development of metabolic syndrome (Artemniak-Wojtowicz et al., 2020). The latter describes a cluster of metabolic complications that increases the risk of developing type 2 diabetes and atherosclerotic cardiovascular disease (CVDs) (Grundy, 2016). Hence, there is need to understand the pathophysiological mechanisms involved in the development of obesity-associated complications, including chronic inflammation and impaired immune response. This is essential to comprehend and establish the effectiveness of currently used interventions.

The use of combined oral contraceptives (COCs) has been associated with an increased risk of arterial and venous thrombosis in women of reproductive age (Zakharova et al., 2011). While the risk of these cardiovascular events are rare in young women, the magnitude of the risk and the effect of different hormonal contents of COC preparations remain unclear (Roach et al., 2015). However, evidence has shown that the use of COC may potentially exacerbate the risk of major adverse cardiovascular events in conditions of obesity (Abdollahi et al., 2003, Pomp et al., 2007). This may be linked with impaired metabolic and exacerbated inflammatory responses which may occur subsequent to the development of major adverse cardiovascular events (MACEs) (Ferreira et al., 2017). Despite the risk for CVDs associated with the use of COC in conditions of impaired metabolism (Simmons and Edelman, 2016), there is still controversy regarding the efficacy of contraceptives in obese individuals in terms of the duration of use, dosage, and generational-type of COC (Trenor et al., 2011).

Of note, estrogen and progesterone are known to play a role in modulating the development and function of both innate and adaptive immune system (Hall and Klein, 2017, Robinson et al., 2014, Toyoda et al., 2011). The modulatory role of these hormones during immune activation may be influenced by the dose and duration of administration (Hall and Klein, 2017, Karpuzoglu-Sahin et al., 2005, Karpuzoglu-Sahin et al., 2001, Priyanka et al., 2013) and their action may also counteract each other (Jain et al., 2004, Toyoda et al., 2011). A previous study on infected ovariectomized female C57BL/6 mice reported on an increased neutrophil count and production of neutrophil chemoattractants proteins following recruitment following estrogen treatment (Robinson et al., 2014). Estrogen and progesterone also modulate macrophage functions (Pisetsky and Spencer, 2011, Toyoda et al., 2011) as well as T cell functions (Lee et al., 2011, Matalka, 2003, Priyanka et al., 2013). For instance, in clinical studies, exogenous estrogen enhanced the production of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) (Kramer et al., 2004), while in a murine model, high concentrations of estrogen suppresses the production of these cytokines by monocyte or macrophage cells (Deshpande et al., 1997). More so, in lipopolysaccharide (LPS)-stimulated dendritic cells in female rats, progestin treatment suppressed the production of TNF-α and IL-1 β in a dose dependent manner (Butts et al., 2007). In contrast, a study by Bouman and colleagues showed that neither exogenous estrogen nor progesterone enhances the production of cytokine in human LPS-stimulated monocytes (Bouman et al., 2004). Taken together, the magnitude by which exogenous estrogen and progesterone modulates the function of both innate and adaptive immune cell remain elusive.

The aim of this study is to determine the impact of COC treatment within rat model of diet-induced obesity (DIO). We further assessed whether switching from a high-fat diet (HFD) to low-fat diet (LFD) restores the levels of immune activation as measured using acute phase reactants such as IL-6 and TNF-α and monocyte chemoattractant protein (MCP)-1.