**5. Tumoral necrosis factor-alpha**

#### **5.1. Tumoral necrosis factor-alpha in human metabolism**

TNF-α is an inflammatory cytokine mainly produced by macrophage cells, but also by other type of inflammatory cells. Among its many roles, TNF-α is an acute inflammatory response protein, which increases C-reactive protein levels and also determines insulin resistance by interacting with insulin receptor [18]. TNF-α plays important roles in regulating lipid metabolism **(Figure 4),** cholesterol metabolism, and adipokine synthesis [61].

**Figure 4.** Effects of TNF-α production of free fatty acids in hepatocytes and adipocytes.

### **5.2. Tumoral necrosis factor-alpha and metabolic syndrome**

TNF-α can be produced by inflammatory cells from the dysfunctional adipose tissue, similar to IL-6. TNF-α is involved in numerous MetS pathways and alterations, in insulin resistance through similar mechanism of mTOR and protein C kinase activation and systemic inflammation [62]. As many studies have shown, TNF-α is being associated with all MetS components.

In the study by Moon et al. on obese adolescents, it was confirmed that TNF-α had higher levels in obese patients, even higher in male subjects, also, TNF-α positively correlated with BMI and waist circumference. Initially, TNF-α correlated positively with triglyceride levels and diastolic blood pressure, and inversely with HDL cholesterol, but after adjustment for BMI and waist circumference, only the association with triglyceride levels persisted [19].

In the meta-analysis of Sookoian et al. conducted on 16 homogeneous studies, it has been shown that obesity, systolic blood pressure, and serum insulin levels positively correlate with TNF-α -308A gene (genetic polymorphism that influences the plasmatic level of cytokine) variant and determine a 23% increased risk to develop MetS [20].

Obesity induces a systemic inflammatory status that determines dysfunctions of the macrophages and adipocytes and inappropriate cytokine production [21]. As a result, higher levels of TNF-α determine insulin resistance through various mechanisms and promote disease progression in patients with MetS **(Figure 5).** Studies emphasize that insulin resistance caused by TNF-α is based on abnormal insulin signaling, overexpression of tissular and plasmatic levels of TNF-α in subjects with insulin resistance, and administration of TNF-α determines and TNF-α neutralization improves insulin resistance [22–25]. Therefore, TNF-α is involved in MetS pathogenesis and progression and could be used in determining patients with MetS.

**Figure 5.** TNF-α and insulin resistance.

**Figure 4.** Effects of TNF-α production of free fatty acids in hepatocytes and adipocytes.

studies confirmed that IL-6 also controls processes involved in the resolution of inflammation,

Studies confirmed that IL-6 is correlated with all five of MetS components. The main explanation relies on the fact that the dysfunctional adipose tissue induces macrophagic proliferation with increased IL-6 production [58]. Weiss et al. have found that IL-6 is associated with hypertriglyceridemia, fasting plasma glucose, and hypertension [59]. The same results are confirmed by Sarbijani et al. [17]. They also reported that increasing levels of IL-6 are correlated with MetS severity [17, 59]. Also, Chedraui et al. found increased levels of IL-6 in women with abdominal obesity, lower levels of HDL-C, and hypertriglyceridemia [18]. Another study demonstrated that high IL-6 levels within hepatocytes in a state of chronic inflamma-

TNF-α is an inflammatory cytokine mainly produced by macrophage cells, but also by other type of inflammatory cells. Among its many roles, TNF-α is an acute inflammatory response protein, which increases C-reactive protein levels and also determines insulin resistance by interacting with insulin receptor [18]. TNF-α plays important roles in regulating lipid metabo-

emphasizing its anti-inflammatory function [57].

tion could be a determining cause of MetS development [60].

**5.1. Tumoral necrosis factor-alpha in human metabolism**

lism **(Figure 4),** cholesterol metabolism, and adipokine synthesis [61].

**4.2. Interleukin-6 in metabolic syndrome**

94 Ultimate Guide to Insulin

**5. Tumoral necrosis factor-alpha**
