IL-12 is one of the most representative members of the Th1 cytokine family, with well-known functions in inducing production of IFN-γ
and differentiation of type 1 T cells, promoting in this way a linkage between innate response and adaptive immunity [13
]. Nevertheless, recent experimental evidence from high-fat-diet-fed mice suggests that IL-12 could have an additional role in the systemic low-grade inflammation and the concomitant advent of obesity-related disorders, such as insulin resistance [14
]. For this reason, it is of much relevance to study the systemic levels of IL-12 in humans that show high metabolic risk, such as obese individuals. In this sense, it has been previously reported that circulating concentrations of IL-12 are significantly increased in subjects with metabolic syndrome [16
] and type 2 diabetic patients undergoing cardiovascular complications [17
]. Furthermore, peripheral blood mononuclear cells (PBMCs) from T2D patients are able to produce higher levels of IL-12 in response to lipopolysaccharide stimulation than those cells from healthy subjects [18
]. In a similar sense, increasing IL-12 secretion has been also observed in human macrophages treated with resistin, a proinflammatory adipokine clearly elevated in obese individuals and T2D patients [15
]. Interestingly, our data demonstrate that circulating levels of IL-12 start to increase in the overweight and have a strong relationship with central obesity, one of the key factors to develop obesity-related disorders such as metabolic syndrome and type 2 diabetes [1
]. Concomitantly, a recent study in a rural population of Mexican women suggests that the risk of having elevated serum IL-12 diminishes in women with high plasma concentrations of zinc, a micronutrient that has been related with a reduced risk for being obese [19
]. In this sense, our results reveal that circulating concentrations of IL-12 increase at the same time that with parameters of obesity, including body mass index, body fat accumulation, and high glucose and triglyceride levels.
An interesting finding in this work is the relationship between serum levels of IL-12 and TNF-α
in overweight and obese individuals. As a classical Th1 cytokine, IL-12 has the ability to induce IFN-γ
production in differentiated T cells [13
]. Interestingly, IFN-γ
has been shown to increase in obese mice and humans [20
]. Thus, in view of the fact that it has been previously demonstrated that IFN-γ
is able to promote releasing of TNF-α
], it is plausible to expect that increasing levels of IL-12 correlate with high TNF-α
levels in obese subjects. Our results seem to be consistent with this hypothesis, since serum IL-12 shows a strong positive relationship with circulating levels of TNF-α
in both overweight and obese individuals. In this low-grade inflammation milieu, TNF-α
has been extensively studied as a key inflammatory factor, capable to impair insulin signaling in murine adipocytes, through activation of negative regulators of the insulin receptor substrate 1-(IRS-1), including p38 mitogen-activated protein kinase and protein-tyrosine phosphatase 1B [22
]. However, the serum levels of cytokines with the ability to induce production of TNF-α
had not been precisely determined in obese humans to date. Therefore, as the low-grade inflammation seems to be determinant in the advent of obesity-related diseases such as type 2 diabetes and AVD [3
], further studies are needed in order to determine the role of IL-12 in the production of IFN-γ
in obese subjects.
On the other side, unexpectedly, we did not observe a significant statistical correlation between serum IL-12 and leptin, despite the fact that leptin showed a clear increase in obese subjects. Nevertheless, it has been shown that leptin does not always correlate with other low-grade inflammation markers. For instance, a previous study conducted in Serb obese women reported a significant augmentation in the plasma levels of the proinflammatory cytokines IL-17 and IL-23, independently of the increase in leptin [23
]. In a similar way, a Th1-immune profile characterized by an increase in the circulating proportion of IFN-γ
-secreting PBMC has been described in Italian obese children, without a significant relationship with leptin levels [24
]. Consistent with previous studies [19
], present results suggest that leptin may not be significantly related with the systemic mild-grade inflammation milieu in this study population. However, additional research taking into consideration the influence of age-, sex-, and ethnicity-associated factors upon leptin levels is required in order to draw major conclusions. A similar result was observed in the absence of significant association of IL-12 with insulin, total cholesterol, and insulin resistance. Regarding this issue, it has been previously reported that the relationship of IL-12 with elevated insulin resistance and dyslipidemia increases in subjects with type 2 diabetes and AVD [17
]. Since we have shown that IL-12 does not seem to have a significant relationship with insulin resistance and total cholesterol in healthy obese subjects, it is probable that IL-12 could be more related with the advent of obesity-related complications than with obesity itself. Nevertheless, further studies using a larger study population of healthy, prediabetic, and diabetic obese subjects are necessary for a more accurate determination of the relationship of IL-12 with insulin resistance and hypercholesterolemia in humans.
Finally, it is worth to mention that serum levels of IL-12 seem to be grouped in two clusters in our study population, characterized by high and low production of IL-12. Interestingly, there are no high producers of IL-12 among normal weight subjects. However, increased production of IL-12 seems to start since the overweight, reaching a plateau in the obesity group. It is important to underline that more than 70% of the high producers of IL-12 also showed increased levels of triglycerides (data not shown). Since there was no difference in the serum levels of IL-12 between women and men (data not shown), we hypothesize that high production of IL-12 may be a marker related to body weight gain and triglyceridemia. Nevertheless, taking into consideration that several factors are able to influence high and low production of cytokines [25
], further research is required to conclude whether body weight gain and triglyceridemia are determinant factors in the production of IL-12 in humans.