Interaction of Osteopontin with IL-18 in Obese Individuals: Implications for Insulin Resistance

Abstract

Background/ObjectiveOsteopontin (OPN) and IL-18 are known inflammatory mediators and both participate in a wide range of biological processes linked to immunological disorders. Since an interaction between OPN and IL-18 has not been studied in obesity, we investigated whether: (i) their levels were simultaneously elevated in obese individuals; (ii) OPN was associated with IL-18 in obese individuals and (iii) their levels associated with fasting blood glucose (FBG) and BMI.Subjects and MethodsPBMCs and plasma samples were isolated from 60 individuals including lean as well as overweight and obese individuals. Subcutaneous adipose tissue samples were obtained. OPN and IL-18 were measured by ELISA. OPN and IL-18 mRNA expression was quantified by real time quantitative RT-PCR.ResultsObese individuals exhibited significantly increased circulating OPN levels as compared with lean individuals (obese 2865±101; lean 1681±116 pg/ml; P<0.0001). IL-18 levels were also high in obese individuals (obese 491±39, lean 301±26 pg/ml; P = 0.0009). OPN and IL-18 expression were simultaneously up-regulated (OPN: 5.4-Fold; IL-18: 8.9-Fold; P<0.05) in PBMCs from obese individuals compared to lean group. Adipose tissue from obese individuals had high expression of OPN (7.3-Fold) and IL-18 (9.6-Fold). Plasma OPN levels correlated positively with FBG levels (r = 0.32, P = 0.02). Similarly, IL-18 correlated positively with FBG levels (r = 0.406, P = 0.0042). Stepwise multiple regression analysis showed an independent association of BMI with OPN and IL-18. Interestingly, OPN levels increased progressively with an increase in IL-18 levels (r = 0.52, P = 0.0004). We also examined the regulatory role of IL-18 in OPN secretion from PBMCs. Neutralizing anti-IL-18Rα mAb reduced OPN secretion.ConclusionThese findings represent the first observation that plasma, PBMC and adipose tissue OPN and IL-18 are simultaneously increased and correlate with each other in overweight/obese individuals which may trigger the development of obesity-associated insulin resistance. Moreover, these results provide the direct evidence that IL-18 regulates OPN production in PBMCs.

Increased circulating osteopontin levels in adult patients with type 1 diabetes mellitus and association with dysmetabolic profile

“…Increased OPN levels were found in obese participants (12,13) and predicted coronary calcification, nephropathy and coronary artery disease in patients with type 2 diabetes, independent of traditional risk factors (14,15).…”

“…Moreover, serum OPN levels were demonstrated to strongly predict incipient diabetic nephropathy (DN), cardiovascular events and all-cause mortality in patients with T1DM (26) and were associated with renal failure and left ventricular hypertrophy in patients affected by systemic hypertension (27,28). Furthermore, in a recent study, obese individuals exhibited significantly increased blood OPN levels and higher adipose tissue/peripheral blood mononuclear cells OPN expression compared with lean individuals; OPN also correlated with fasting blood glucose (FBG) and BMI (13).…”

Wogonin suppresses osteopontin expression in adipocytes by activating PPARα

“…However, these two studies have demonstrated that fat loss produced a statistically significant reduction in circulating OPN concentration [43,44] . In addition, high levels of serum OPN were found in obese individuals [42,43,45] . These findings suggest that adipocytes may be one origin of circulating OPN levels.…”

The pathophysiological basis of bone tissue alterations associated with eating disorders

“…Finally, more recently, simultaneous up-regulation of IL-18 and OPN in peripheral blood mononuclear cells (PBMCs) has been reported in obese individuals as compared to lean subjects. Intriguingly, treatment with a neutralizing IL-18 antibody diminished OPN secretion from PBMCs, indicating that IL-18 regulates OPN expression [137]. These findings point toward a specific pathophysiological role of OPN also in human inflammatory processes linked to obesity-induced adipose inflammation, insulin resistance, type 2 diabetes and its complications.…”