The ongoing rise in global obesity prevalence has recently reached pandemic proportions1. Childhood obesity, in particular, presents a critical public health concern as it is associated with future development of cardiovascular disease (CVD) and Type 2 Diabetes (T2D). Thus, early management of childhood obesity and detection of subclinical pathology is critically required to mitigate disease progression and improve health outcomes.
CV-associated risk is typically determined using markers of lipid metabolism, such as triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in a fasted individual. However, these lipid markers have two key limitations: 1) fasting triglycerides and LDL-C are not sensitive in assessing CV risk in children, and 2) fasting biomarkers may not accurately represent normal metabolism since people are most often in the fed state. Consequently, there has been a recent paradigm shift to measuring lipids when non-fasted or following a meal (i.e., postprandially)2,3. Having abnormal lipid and lipoprotein levels, termed dyslipidemia, is a key CVD risk factor and can be assessed at fasting or postprandially. In fasting dyslipidemia, very-low-density lipoprotein particles are overproduced from the liver, and their accumulation contributes to the formation of small dense LDL-C (sdLDL) and reduced HDL-C. Whereas in postprandial dyslipidemia, intestinal triglyceride-rich lipoproteins (TRLs), or chylomicrons, are overproduced, which ultimately contributes to an accumulation of chylomicron remnants. The buildup of both sdLDL and chylomicron remnants in the sub-endothelial space contributes to CVD risk. Notably, this accumulation also promotes inflammation to facilitate plaque formation on arterial walls (i.e., atherogenesis).
Assessing postprandial lipids may offer several clinical benefits over fasting markers. First, postprandial dyslipidemia is an independent risk factor for CVD4,5, and strong evidence suggests that non-fasting triglycerides may better predict CVD and mortality compared to fasting levels4. In addition, non-fasting blood tests reduce patient burden and increase compliance. Accordingly, recent Canadian guidelines have begun adopting non-fasting lipid profiling in adults. However, there is an evidence gap in assessing postprandial dyslipidemia in children and teenagers for novel biomarkers. Such investigations are critical to facilitate early detection and management in high-risk adolescents.
The Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) program recently initiated a study of 45 adolescents with and without obesity to assess the relationship between postprandial dyslipidemia and intestinal regulators of lipid metabolism (i.e., glucagon-like peptides [GLPs] and bile acid species)6. Participants completed an oral fat tolerance test, where they consumed a high-fat meal and underwent blood sampling at specified time points to permit evaluation of postprandial lipid metabolism. Higgins et al. found that adolescents with obesity exhibited both fasting and postprandial dyslipidemia, mainly characterized by increased postprandial levels of large TRLs. Postprandial profiling exaggerated what was already evident at fasting or revealed abnormalities in obesity that fasting levels masked. Furthermore, Higgins et al. showed that dyslipidemia was paralleled by reduced postprandial bile acid levels and co-secretion of GLP-1 and GLP-2. Notably, these markers strongly correlated with insulin resistance (IR).
Given these findings, we recently expanded this study to broad inflammatory profiling to identify novel biomarkers in at-risk adolescents. In both fasted and postprandial states, we found that adolescents with obesity and IR had increased interleukin (IL)-6 and serum calprotectin levels compared to lean participants. In addition, we observed a strong association between postprandial pro-inflammatory markers (i.e., calprotectin, IL-6, IL-18, and tumour necrosis factor-α) and markers of adiposity, IR, lipids, systemic inflammation, and/or hepatic injury. Both IL-6 and tumour necrosis factor-α are secreted directly from adipose tissue and have been shown to inhibit insulin receptor substrates, which may explain their role in obesity-related IR. Alternatively, calprotectin is typically sampled from stool as a biomarker of gut inflammatory disorders (e.g., inflammatory bowel disease). However, calprotectin in serum was recently postulated as a novel tool in assessing obesity. Together, these data underscore the close association between inflammation and obesity- and IR-related pathogenesis. Although many of these markers are not used clinically, their utility has been shown in numerous fields (e.g., SARS-CoV-2), prompting consideration for clinical implementation.
In addition, we performed metabolomics profiling using nuclear magnetic resonance spectroscopy and uncovered diverse postprandial patterns between study groups, particularly among amino acids. In agreement with previous studies, levels of branched-chain amino acids (BCAAs) and alanine were elevated in obesity and moreso in those with IR. Notably, despite elevated concentrations in obesity, the postprandial response was depressed compared to lean subjects, suggesting a marked aberration in postprandial metabolism. These amino acids were also strongly associated with fasting and postprandial dyslipidemia and IR. However, why and how amino acids are dysregulated in obesity remains inconclusive. Our study may support one predominant theory, which explains that BCAA catabolism is likely impaired in obese states, leading to a buildup in circulation. In turn, this toxic buildup of BCAAs and their metabolites triggers mitochondrial dysfunction and stress signaling associated with IR and T2D7.
Taken together, adolescents with obesity and IR exhibit significant fasting and postprandial dysregulation of several inflammatory and metabolic markers integral to lipid metabolism. These data add to our understanding of obesity-related pathogenesis and may reveal novel biomarkers for early metabolic and cardiovascular diseases, such as postprandial dyslipidemia, in at-risk teenagers. Such investigations are essential to facilitate early detection and management of obesity-related conditions in pediatrics. Importantly, this work emphasizes the potential added clinical utility of postprandial profiling in assessing cardiometabolic diseases.
- The Lancet Gastroenterology & Hepatology. Obesity: another ongoing pandemic. Lancet Gastroenterol Hepatol. 2021;6(6):411. doi:10.1016/S2468-1253(21)00143-6
- Wang Y, Pendlebury C, Dodd MMU, et al. Elevated remnant lipoproteins may increase subclinical CVD risk in pre-pubertal children with obesity: a case-control study. Pediatr Obes. 2013;8(5):376-384. doi:10.1111/J.2047-6310.2012.00116.X
- Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: Clinical and Laboratory implications including flagging at desirable concentration cutpoints-A joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Clin Chem. 2016;62(7):930-946. doi:10.1373/clinchem.2016.258897
- Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. J Am Med Assoc. 2007;298(3):309-316. doi:10.1001/jama.298.3.309
- Nordestgaard BG, Benn M, Schnohr P, Tybjærg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. J Am Med Assoc. 2007;298(3):299-308. doi:10.1001/jama.298.3.299
- Higgins V, Asgari S, Hamilton JK, et al. Postprandial dyslipidemia, hyperinsulinemia, and impaired gut peptides/bile acids in adolescents with obesity. J Clin Endocrinol Metab. 2020;105(4):1228-1241. doi:10.1210/clinem/dgz261
- Siddik MAB, Shin AC. Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond. Endocrinol Metab. 2019;34(3):234-246. doi:10.3803/ENM.2019.34.3.234