Obesity, a complex chronic disorder characterized by the enlargement of adipose tissue, has a multifactorial etiology, involving genetics, hormones, diet, and environment. Adipose tissue was considered as an inert tissue responsible for energy storage; however, it is now recognized as an active tissue in the regulation of inflammation [1]. Obesity is associated with alterations in immunity in which there are elevated levels of circulating pro-inflammatory cytokines. As visceral adipose tissue (VAT) expands, macrophages are recruited to the tissue, leading to the production and release of several adipokines and cytokines. This includes leptin, adiponectin, resistin, and visfatin, as well as interleukin (IL)-4, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-6, and several others [2, 3]. Pro-inflammatory molecules produced by VAT have been implicated as an active participant in the development of metabolic disease such as type 2 diabetes (T2D) and cardiovascular disease (CVD) [4].
Obesity increases cardiovascular risk by increased fasting serum triglycerides (TG), high LDL cholesterol, low HDL cholesterol, elevated blood glucose and insulin levels. These conditions are mainly developed due to excessive caloric intake and high fat diet (HFD). Serum lipid variances are common attributes of metabolic syndrome and may be correlated to a pro-inflammatory gradient. An important connection between obesity, metabolic syndrome and dyslipidemia, may be the development of insulin resistance (IR) in tissues such as the liver. This leads to an influx of circulating fatty acids due to dietary sources, the breakdown of fat in the blood vessel and resistance to the anti-lipolytic effects of insulin [5]. All of these conditions result in increased circulating lipids and cholesterol particles in the blood. Entry and retention of LDL particles in the arterial wall trigger inflammatory signals, resulting in the expression of adhesion molecules by the endothelium and the local secretion of cytokines and chemokines. Ultimately, an increase in circulating lipids contributes to the accumulation of macrophages and other inflammatory cells in the subendothelial space [6, 7].
Interleukin-3 (IL-3) belongs to the β common cytokine family, in addition granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and IL-5. IL-3 plays a role in leukocyte development. This cytokine is largely used for steady-state hematopoiesis but is also produced at sites of inflammation and therein exert pathophysiologic effects. The β common chain family of cytokines regulate various inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. A previous study indicated that an HFD induced central and peripheral high leukocyte count and circulating neutrophils levels in rats [8]. The HFD animals had a higher number of bone marrow cells, which had a greater capacity to produce IL-3 and G-CSF [8]. It appears that HFD has an indirect effect on the levels of IL-3. The increased circulation of leukocytes has been reported in obese individuals as well as individuals with features of metabolic syndrome, coronary artery disease and complications from T2D [9–12].
Interleukin-7 (IL-7) is a cytokine essential for cell survival and proliferation of both naïve and memory T cells [13]. IL-7 binds to interleukin-7 receptor alpha (IL-7Rα) and γc, activating JAK/STAT and AKT signaling pathways. Non-hematopoietic and dendritic cells produce IL-7; moreover, normal adult human hepatic tissues produce IL-7 transcripts and proteins. A lack of IL-7Rα in humans has, been known to exhibit severe combined immunodeficiency [14]. Polymorphisms in IL-7R are risk factors for several involved in excess immune and inflammatory responses. IL-7 is markedly increased in the serum of obese individuals. IL-7R is overexpressed in white adipose tissue (WAT) in obesity; a previous study measured the metabolic outcomes of IL-7R knockout (KO) mice on chow and HFD [15]. The expression of genes and proteins related to IR and inflammation were evaluated in WAT. They found that IL-7R KO mice exhibited significantly less weight gain and visceral fat compared to wildtype controls on both chow and HFD [15]. Overall, the IL-7R KO mice has less adipogenesis signaling, pro-inflammatory cytokine production and macrophage infiltration in the WAT. These results imply that HFD may activate pro-inflammatory production and release, including IL-7. IL-7 has also been implicated in the progression of atherogenesis by recruiting monocytes/macrophages to the endothelium [16]. Both innate and adaptive immunity have been suggested to modulate the rate of lesion progression. Atherosclerosis is characterized by the infiltration of immune cells and the presence of lipid-enriched macrophages in the arterial wall and is a major cause of CVD.
The immune system plays a major role in the development and progression of CVD and T2D. Among mammals, males and females differ in their innate immune responses, which suggests that some sex differences may be germline encoded. The number and activity of cells associated with innate immunity differ between the sexes; males have high natural killer cells frequencies than females [17]. Neutrophils and macrophages have higher rates of phagocytosis in female than males [18]. Sex influences multiple aspects of adaptive immunity as well. The thymus plays an essential role in the development of the adaptive immune system by generating the peripheral T cell pool. Adolescent male rats have larger thymuses, greater thymocyte levels and a difference in distribution of thymocyte subsets in comparison to female rats [19, 20]. In addition, adult humans have sex differences in lymphocyte subsets: B cells, CD4 + T cells and CD8 + T cells. These differences are observed across multiple ethnic groups as well, including Europeans, Asians, and Africans [19–21].
Sex chromosome genes and hormones which includes estrogens, progesterone and androgens, influence differential regulation of immune responses between males and females. In addition, women have different sex steroid concentrations and X chromosome diploidy which plays a significant role [22]. Although infant and childhood males produce higher inflammatory responses than females, after puberty inflammatory responses are consistently higher in females than in males [23]. Sex differences in immune responses are altered throughout life and are influenced by both the age and reproductive status. As humans age, concentrations of sex steroids decline rapidly for females and more gradually in males. Thus, males in reproductive senescence tend to have an increased inflammatory response than females [24]. Immunological differences between sexes reflect hormonal, genetic and environmental effects on the immune system that can change throughout life in humans. Despite a growing body of evidence demonstrating sex-based differences in immune responses, fewer than 10% of immunology articles analyze data by sex in previously published papers [25].
Inflammation is rampant in obesity due to the expansion of VAT leading to IR in metabolic and peripheral tissue resulting in T2D. Inflammatory cytokines also play a major role in the progression of T2D and diabetic complications. This study was designed to investigate the influence of high HbA1c on IL-3 and IL-7 serum levels of obese, African American women and obese, African American men. African Americans are the most at risk population for obesity and T2D and would benefit greatly from this study. To eliminate obesity as a confounding factor of cytokine levels, both the control and experimental groups were obese for males and females. We also investigated the relationship between IL-3 and IL-7 levels and clinical metabolic parameters. Herein, we present data showing serum IL-3 and IL-7 levels increase in obese African American women with high HbA1c in comparison to control group. We also observe a decrease in serum IL-3 and IL-7 levels in obese, African American males with high HbA1c in comparison to control group. In addition, several clinical metabolic parameters are correlated with these key inflammatory cytokines.