We can define obesity as an energy imbalance, and for purposes of this chapter base it upon the body mass index, a representation of the body weight or mass adjusted for height. BMI is measured as the ratio of kilograms per meter squared (kg/m²). The calculation of ones BMI is relatively simple and several tools are available on the web. Here is one that was programmed by this author (http://​touchcalc.​com/​bmi). A BMI of greater than 25 kg/m² is considered overweight, and if over 30 kg/m² obese. The concern lies in strong observational data that links an elevated BMI to both cardiovascular disease and type 2 diabetes, but what is even more concerning comes from long-term follow-up studies of adolescents with high normal BMI ranges. An Israeli study demonstrated those in the high normal 50th–74th BMI percentiles had had a graded risk for death. The hazard ratio (HR) for persons in the 95th BMI percentile when compared with those in the 5th–24th percentiles was 4.1 (95% CI 3.1–5.4) for death from coronary artery disease during a follow-up period of 30–40 years [7]. There are two forms of obesity, truncal and visceral. In truncal obesity, adipocytes store free fatty acids and become engorged. In visceral obesity, however the fatty acids are first accumulated by the liver and then stored in the abdominal area. Visceral obesity has a higher risk of causing cardiovascular disease.

Inflammation , in its broadest sense, is a mechanism the body uses to respond to an “attack” and to initiate repair, particularly from what it considers a foreign body such as a bacteria or a virus. Inflammation can also be triggered by obesity, and in this circumstance, is a low-grade insidious process. The inflammatory process associated with obesity is widespread, affecting the liver, pancreas, heart, brain, and muscle, in addition to adipocytes. In many disease states, the insidious inflammatory response leads to further harm in these tissues. The story of obesity and inflammation starts with the adipocyte (fat cell), which in addition for being a repository for free fatty acids, shares in the control of several metabolic processes, playing roles in the regulation of inflammatory mediators, iron, the appetite, lipids, and sugar. Overexpression of inflammatory and macrophage genes occurs when adipocytes are exposed to obesity and undergo a remodeling process. The presence of obesity recruits and then stimulates the macrophages interspersed with the adipocytes to release of inflammatory cytokines. The fat cell also releases adipokines that play key roles in an autocrine, paracrine, and endocrine fashion. The two most studied adipokines are adiponectin and leptin.

Adiponectin is a 224-amino-acid collagen-like protein that is related to complement factor C1q and its C-terminal domain is similar to tumor necrosis factor alpha (TNF-α). It is often referred to in the literature as Acrp30. It is secreted from adipocytes, particularly in anorexia, and circulates in plasma, increases the oxidation of free fatty acids (FFA) in many tissues, especially skeletal muscle where it interacts via adiponectin receptor 1 and the liver where it interacts through adiponectin receptor 2. It leads to accumulation of free fatty acids inside the adipocyte, and clears free fatty acids from the circulation. Fat oxidation is mediated by adiponectin activation of AMP-activated protein kinase. This enzyme increases glucose transport into muscle and can be activated by exercise. It improves insulin resistance through the PPAR-α (peroxisome proliferator-activated receptor alpha) pathway. Exercise training may increase adiponectin receptors [8, 9].

Adiponectin increases insulin sensitivity and low adiponectin levels are associated with obesity, type 2 diabetes, and decreased FFA entering the subcutaneous adipocyte. The metabolic disease occurs as excess FFAs are deposited in other locations. Adiponectin levels fall in truncal obesity, and are also low in association with visceral obesity. As the levels fall, insulin resistance increases as do markers of inflammation. Lower adiponectin levels have been implicated in the relationship between macrophages and atherosclerosis. Thus, lowered levels of adiponectin are associated with cardiovascular disease and myocardial infarction [8]. Low adiponectin levels are correlated with elevated C-reactive protein, IL-6, the production of TNF-α and the inhibition of Nuclear factor-κB (NF-κB) signaling. High levels of adiponectin promote IL-10 which blocks inflammation.

The pathogenesis of this relationship is just becoming clearer and a strong relation between adiponectin and metabolic disorders such as type 2 diabetes with macrophage regulation and chronic low-grade inflammation are apparent. Monocytes from the bone marrow are recruited to adipose tissue by adipokines and differentiate into macrophages. There are two phenotypes of macrophages , M1 and M2, and their respond to different cytokines can change their phenotype. M1 macrophages are anti-inflammatory, while M2 type are proinflammatory. Macrophages infiltrate into adipose tissue and when polarized into a proinflammatory M2 phenotype reduce adiponectin receptor 1 and 2 expression, but when proinflammatory stimuli are altered and the M1 phenotype expressed, the adiponectin receptor is upregulated [10].

The presence of iron inside the adipocyte decreases adiponectin production. In type 2 diabetes, a low adiponectin state, adiponectin is inversely related to serum ferritin. An increase in iron inside the adipocyte is associated with decreased adiponectin mRNA and regulates adiponectin transcription.

Like the macrophage and the enterocyte, adipocytes have an iron exporter, ferroportin. Ferroportin is responsible for shuttling iron out of the cell. When ferroportin decreases, cells such as adipocytes, macrophages, and enterocytes load with iron. In the adipocyte, this iron loading has been demonstrated to decrease adiponectin [11]. The amount of iron in the adipocyte also regulates leptin and food intake.

Leptin is a member of helical cytokines, and its membrane receptors are structurally like the receptors on cytokines. IL-6 and leptin receptors have some subunits in common. It was the first adipokine discovered and has a direct effect on the hypothalamus to reduce appetite and control food intake. In obesity, leptin concentrations increase, but target cells become resistant to its action [8].

Increasing dietary iron intake enhances the appetite and lowers serum leptin levels. This has been shown independent of inflammation and was demonstrated in a study of 75 subjects who had serum leptin levels that were inversely associated with serum ferritin (Pearson’s r = −0.396, P = 0.0004). Ferritin is an intercellular protein capable of storing and binding iron. Small amounts secreted serum function as an iron carrier.

Dietary iron overload increased iron accumulation in adipocytes by 115% in mice, and in turn decreased leptin mRNA. Serum leptin levels decreased with iron loading (Pearson’s r = −0.26, P = 0.001). Iron increased phosphorylation of the cAMP-Responsive Element Binding Protein (CREB) and decreased activity in leptin promoter region. Through this dual action, feeding effects on metabolism were exhibited; iron influenced mice eating behavior. After a 9–12-week period, mice fed a high iron chow ate more during each 15-min feeding interval over a 3-day period when studied in a metabolic chamber (P < 0.0001) [12].