**2. Leptin, adiponectin, and leptin:adiponectin ratio**

#### **2.1. Leptin**

Leptin is a hormone produced mainly by white adipose tissue, but also by non-adipose ones (placenta, stomach, mammary gland, and immune system) [40, 41]. Its regulation is achieved through various factors dependable on the metabolic status (**Figure 1**). Thus, the implications of leptin in pathogenic mechanisms comprise energy homeostasis, obesity syndromes, metabolic dysfunctionalities, neuroendocrine function, and bone metabolism. The pathogenic pathways of leptin follow similar targets through different mechanisms [40]. Leptin binds to its functional receptor and activates several transduction pathways, such as Janus kinase (JAK)/signal transducers and activators of transcription (determines autophosphorylation of JAK1 and JAK2 with STAT3 activation), mitogen-activated protein kinase (activates this MAPK pathway in central and peripheral tissues), phosphatidylinositol-4,5-bisphosphate

**Figure 1.** Factors that regulate leptin plasmatic levels.

3-kinase/protein kinase B (leptin activates directly PI3K in peripheral tissue), and AMPactivated protein kinase [42, 43].

Since its discovery, many studies have focused on the role of leptin in the evaluation of cardiovascular risk. High levels of leptin lead to a global and/or selective leptin resistance. MetS is a condition that favors leptin resistance through systemic inflammation, insulin resistance, hyperlipidemia, hypertension, atherosclerosis, and obesity [44]. Leptin levels correlate mainly with obesity and waist circumference, as it has been confirmed in numerous studies, the aspects of which are detailed in **Table 1** [4–8].

#### **2.2. Adiponectin**

cardiovascular disease [2]. Recent studies have shown that, being involved in MetS pathogenesis, some adipokines, neuropeptides, inflammatory cytokines, prothrombotic factors, and

Various studies confirmed that the leptin:adiponectin ratio (LAR) could have a superior predictive power in determining insulin resistance and MetS severity than the use of leptin or adiponectin alone [3]. Leptin is positively correlated with obesity and waist size [4–8]. Adiponectin has important physiological functions in maintaining metabolic balance and is inversely related with MetS components independently of body mass index (BMI) [7, 9].

Ghrelin is inversely correlated with MetS components, and studies confirmed its role in MetS prediction. Also, a positive correlation of ghrelin levels with hypertension, insulin resistance,

Regarding the pro-inflammatory cytokines, studies confirmed that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) are positively correlated with hypertriglyceridemia, hypertension, fasting glucose levels, insulin resistance, and in postmenopausal women with central obesity [17, 18, 19–25]. Oxidized low-density lipoprotein (LDL) levels have been found to be correlated with insulin resistance, hyperinsulinemia, impaired glycemic control, and

Recent studies also confirmed that novel biomarkers such as pentraxin-3 are positively correlated with MetS severity and the presence of vascular lesions, and it could bring new data on the MetS mechanism. Also, pentraxin-3 (PTX3) was found to be correlated with low high-

Paraoxonase-1 (PON-1) was inversely correlated with the presence of MetS, more precisely with central obesity, hypertriglyceridemia, and hypertension [32–35]. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, and decreased levels of IL-10 are associated with insulin

Leptin is a hormone produced mainly by white adipose tissue, but also by non-adipose ones (placenta, stomach, mammary gland, and immune system) [40, 41]. Its regulation is achieved through various factors dependable on the metabolic status (**Figure 1**). Thus, the implications of leptin in pathogenic mechanisms comprise energy homeostasis, obesity syndromes, metabolic dysfunctionalities, neuroendocrine function, and bone metabolism. The pathogenic pathways of leptin follow similar targets through different mechanisms [40]. Leptin binds to its functional receptor and activates several transduction pathways, such as Janus kinase (JAK)/signal transducers and activators of transcription (determines autophosphorylation of JAK1 and JAK2 with STAT3 activation), mitogen-activated protein kinase (activates this MAPK pathway in central and peripheral tissues), phosphatidylinositol-4,5-bisphosphate

excessive adipose tissue and could predict the occurrence of MetS [26–28].

density lipoprotein (HDL) cholesterol levels and high triglycerides [29–31].

**2. Leptin, adiponectin, and leptin:adiponectin ratio**

others could be used in diagnosing and monitoring these patients.

and obesity has been found [10–16].

90 Ultimate Guide to Insulin

resistance and the presence of MetS [36–39].

**2.1. Leptin**

Adiponectin is a protein hormone produced exclusively by adipocytes. Its high-molecular weight form is proved to have the most intense metabolic activity. Circulating levels of adiponectin are higher in females than in males due to the stimulating activity of testosterone on adiponectin secretion [45]. It plays an important role in metabolic balance, and its lower levels are correlated with an increased cardiac, vascular, and metabolic risk.


**Table 1.** Leptin correlations with metabolic syndrome.

This hormone acts directly on hypothalamus and indirectly by increasing the expression of orexigenic peptides such as neuropeptide Y, Agouti-related protein, proopiomelanocortin,

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In addition to its effect on hunger, ghrelin has important effects on glucose homeostasis, energy homeostasis, heart, muscular atrophy, bone metabolism, and tumors [53]. Recent studies emphasize that AG excess is correlated with insulin resistance and metabolic altera-

Ghrelin is inversely associated with MetS components, and progressively lower ghrelin levels are being correlated with its severity. Ukkola O et al. emphasized the correlation of low ghrelin levels in obese patients with metabolic syndrome [55]. Also, the positive correlation of ghrelin levels with hypertension, insulin resistance, and obesity has been confirmed by numerous studies. McLaughlin et al. have concluded that ghrelin correlates with MetS mainly based on obesity as well as they identified lower ghrelin levels in patients with MetS and obesity than in non-obese MetS patients [10]. Likewise, many studies confirm the relation

IL-6 is a human cytokine that plays important roles in acute and chronic inflammation, immune cell development, and the pathogenesis of autoimmune disease. It is known that the increased activity of IL-6 gene is associated with an elevated risk of developing diabetes mellitus [56]. Likewise, IL-6 is linked with all the components of the inner immunity and yields a pro-inflammatory effects explained by different pathways **(Figure 3)**. Nevertheless,

tions; thereby, the AG/UAG ratio could play a role in the development of MetS [54].

and corticotropin-releasing hormone [52].

**3.2. Ghrelin and metabolic syndrome**

between MetS and ghrelin [11–16].

**4.1. Interleukin-6 and inflammation response**

**Figure 3.** Inflammation pathways that involve IL-6.

**4. Interleukin-6**

**Figure 2.** Metabolic balance mediated by adiponectin.

In normal subjects, adiponectin has important physiological functions in maintaining the metabolic balance (**Figure 2**); therefore, in patients with MetS, adiponectin levels are decreased [43]. Numerous studies have demonstrated its positive effect on metabolic protection, mainly based on its potentially inhibitory activity on the atherogenic process [46]. Recent studies have shown that adiponectin is inversely correlated with MetS components and that it has benefic effects on metabolic disorders [47]. Hypoadiponectinemia induced by visceral obesity determines vascular changes and insulin resistance. Likewise, two clinical studies conducted by Gannage-Yared et al. and by Santaneimi et al. have demonstrated the correlation of adiponectin with MetS independent of BMI [7, 9].

#### **2.3. Leptin:adiponectin ratio**

Various studies recommend using the leptin:adiponectin ratio (LAR) due to its increased predictive power, despite determining leptin and/or adiponectin alone. Recent data suggest the fact that leptin and adiponectin are two molecules that possess antagonistic effects. In addition, the study by Thorand et al. has been suggested that leptin and adiponectin interact with each other in order to modulate the risk of diabetes [3]. Therefore, Finucane et al. have demonstrated that LAR is a useful marker of insulin resistance in non-diabetic adults [48]. Lopez-Jaramillo et al. have emphasized the use of LAR in the evaluation of insulin resistance, and Kotani et al. have confirmed the predictive value of LAR in Japanese patients with MetS; other studies have also shown the correlation between LAR with all five MetS components [49–51].
