ReviewObesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: A need for screening tools to target interventions
Introduction
The increasing incidence of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) worldwide has raised interest in means of early identification of risk and preventative treatment in those with multiple risk factors [1]. A major factor in the increase in these adult chronic diseases has been the obesity epidemic: compared with those of normal weight, adults who are obese have a 50% to 75% increased risk of CVD over 3- to 14-y periods [2], whereas obesity starting in childhood carries a higher risk of adult CVD and T2DM [3]. These risks make childhood obesity a logical target for intervention. Nevertheless, not all obese individuals carry the same risk for future disease, which is encapsulated in the concept of the “healthy obese,” a subset of obese children and adults who do not exhibit increases in CVD risk factors [4], [5]. In addition, outside of intensive lifestyle interventions as part of research protocols, attempts at weight loss for children and adolescents in clinical settings have been modest [6], [7], [8]. This raises a question about the need for tools to identify risk for future disease—tools that could be used to trigger more intensive intervention in a subset of children at higher risk.
Currently, there are few evidence-based tools available for use in risk stratification in pediatrics. Such tools could end up being factors related to the underlying processes that connect obesity to future disease. One set of such processes is the metabolic syndrome (MetS), a cluster of CV factors, including central obesity (as assessed by increases in waist circumference), hypertension, increased fasting blood glucose, high levels of triacylglycerols, and low high-density lipoprotein cholesterol [9], [10], [11]. MetS itself represents a potential screening tool for risk in adolescents [12] but is not widely used clinically, likely because of its complexity of use, requiring that patients have increases above specific cutoff values in at least three of the five components of MetS [13]. In this sense—if possible—a single blood test would likely represent an easier clinical tool. A further drawback is that MetS exhibits racial/ethnic differences in its accuracy [14].
Another important target for risk-related screening is obesity-related inflammation. One inflammation-associated screening tool that is used for risk stratification in adults is high-sensitivity C-reactive protein (hsCRP). Higher levels of hsCRP have been linked to risk for CVD and T2DM in adults [15], [16], [17], [18], [19], [20], [21], although no such long-term data are available in adolescents. In this review, I will consider the processes underlying the connections among obesity, inflammation, and adult disease; the data for hsCRP as a screening tool for future CVD and T2DM in adults; and data regarding obesity-related inflammation in children. Using this as background, I will consider multiple potential screening tools that in the future may be used to identify obese adolescents at highest risk for future CVD and T2DM.
Section snippets
Obesity and systemic inflammation
The concept of obesity as an inflammatory state has continued to develop over the past 15 y, and as our understanding of the process has progressed, multiple factors have been identified that may serve as reasonable screening tools. The model (Fig. 1) that has emerged from multiple studies features adipocytes—and in particular visceral adipocytes—as playing important endocrine roles in the process of inflammation and worsening insulin sensitivity [22]. In response to excess lipid stores,
Inflammation and insulin resistance
Another important consideration in the potential use of obesity-related inflammation for risk determination is its link to insulin resistance. Insulin resistance refers to the inability of physiologic levels of insulin to produce the movement of glucose into the cells. Although the underlying molecular processes involved in insulin resistance continue to be described, it is clear that multiple factors contribute to systemic insulin resistance, including genetics, visceral obesity, low levels of
Inflammation and CVD
In addition to its relation to insulin resistance and T2DM risk, systemic inflammation has been even more notable as a marker of CVD risk in adults. Indeed, it has been pointed out that 1) many of the best-known CVD risk factors (smoking, hypertension, and hyperglycemia) promote noxious stimuli that lead to the production of leukocyte adhesion molecules and 2) this promotes an inflammatory response that is part of the mechanism of atherosclerotic plaque formation and growth [51]. Monocytes that
hsCRP as a risk assessment tool in adults
Thus far, the data linking hsCRP and disease risk come entirely from adult studies. Multiple cohort studies including adults as young as 40 y old over follow-up time frames of 3 to 18 y have demonstrated consistent relations between increased hsCRP and risk for future CVD (Table 1) [33]. When subjects were divided into quartiles or quintiles of hsCRP, those with in the highest category of hsCRP had adjusted relative risks of 2.3 to 4.8 for CVD events compared with the lowest category, even
Consideration of hsCRP as a risk assessment tool in adolescents
Although longitudinal data regarding the predictive importance of hsCRP in adolescents are lacking, inferential data support the potential for such a relation. As in adults, hsCRP levels in childhood are increased in the settings of obesity and are strongly associated with waist circumference, body mass index, and adiposity, as summarized in Table 2 [59], [60], [61], [62], [63]. With respect to insulin resistance, levels of hsCRP levels are strongly associated with measurements of insulin
Consideration of other potential screening tools in adolescents
Although hsCRP may not yet be the correct tool to use in identifying adolescents at higher risk for adult disease, such tools may prove beneficial, particularly as a motivator for obese adolescents and their treating physicians. In the National Weight Control Registry of individuals who have lost at least 13.6 kg of weight and kept it off for at least 1 y, 83% reported a trigger that started their lifestyle intervention in earnest and for 23% this trigger was a medical reason, such as a
Conclusion
Many of the processes leading to CVD and T2DM are present already in childhood, although the likelihood of developing disease appears higher for some adolescents than others. Screening adolescents for MetS-related risk for CVD and T2DM may help in identifying individuals at particularly great need for lifestyle modification. hsCRP is used as such a screening tool in adults of intermediate risk for CVD to trigger more immediate intervention. However, although data regarding hsCRP and other
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2022, PharmaNutritionCitation Excerpt :This process may lead to an activation of NF-κB (nuclear factor-kappa B) and downstream pro-inflammatory genes involving TNF-α (tumor necrosis factor-alpha), IL-6 (interleukin-6), and MCP-1 (monocyte chemoattractant protein-1) and a reduction of anti-inflammatory genes, like adiponectin and IL-10 [8]. Furthermore, adipogenesis stimulates monocytes into adipose tissue and activates their differentiation into macrophages that produce pro-inflammatory cytokines and chemokines, such as TNF-α, IL-6, IL-1β, resistin, leptin, and other markers that will potentiate the inflammation process [2,3,9]. In addition, obesity can increase the systemic oxidative stress through biochemical mechanisms, such as superoxide generation from NADPH oxidases (Nicotinamide Adenine Dinucleotide Phosphate oxidases), oxidative phosphorylation, and protein kinase C activation.
This work was supported by grants 5K08HD060739-03 and 1R21DK085363 from the National Institutes of Health.