Hepatic Fat Accumulation Is Modulated by the Interaction between the rs738409 Variant in the PNPLA3 Gene and the Dietary Omega6/Omega3 PUFA Intake

A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake.We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing.As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively).These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype

The adipose tissue expandability hypothesis: a potential mechanism for insulin resistance in obese youth.

Obesity has become a major global health challenge of the 21st century, as it is associated with the onset of type 2 diabetes (T2D) and cardiovascular complications, even at a very early age in life. The root causes of pediatric obesity remain incompletely understood. The obesity epidemic together with the relationship of obesity to the growing population burden of chronic disease presents unprecedented research opportunities and challenges. Decades of obesity-related research funded by governments around the world have yielded many important discoveries about both etiological pathways and preventive or therapeutic interventions. Yet, there is a sense that the problem is outpacing these research efforts. Obesity poses a significant risk for the development of cardiovascular disease (CVD) , diabetes and certain cancers thereby shortening life expectancy. Nevertheless, many obese individuals do not develop any of these comorbidities. One hypothesis explaining this dilemma is that total body fat is not the culprit of adverse health in obesity rather the relative proportion of lipids in various fat depots is what determines the metabolic risk. In this review, we describe the role of altered fat partitioning in youth onset obesity and its relation to fatty liver and T2D during adolescence. Horm Mol Biol Clin Investig 2018 Mar 29; 33(2):20180005

Adipose insulin resistance in obese adolescents across the spectrum of glucose tolerance

CONTEXT: Adipocytes represent an important insulin-responsive tissue taking an active part in glucose metabolism. OBJECTIVE: This study sought to assess adipose tissue insulin resistance (IR) across the spectrum of glucose tolerance and to test its relation with free fatty acid (FFA) suppression during an oral glucose tolerance test (OGTT). DESIGN AND SETTING: A cross-sectional analysis of a pediatric clinic–derived cohort of obese adolescents. PATIENTS OR OTHER PARTICIPANTS: Participants age 7–20 y with a body mass index that exceeded the 95th percentile for their age and sex. INTERVENTION(S): A standard oral glucose tolerance test. MAIN OUTCOME MEASURES: The adipose tissue insulin resistance index (calculated as the product of fasting insulin and FFA concentrations) (Adipose IR) and the area under curve of FFAs during the OGTT were compared between glucose tolerance categories. RESULTS: A total of 962 obese children and adolescents participated in this study. Adipose IR significantly increased across glucose tolerance categories (P for trend < .001). Within the normal glucose tolerance participants, an increase in adipose IR was observed related to an increase in 2-hr glucose levels. In a subsample of participants who underwent abdominal imaging for determination of lipid partitioning (n = 115), a tight relation of visceral fat (r = 0.34; P < .001) and the visceral/sc fat ratio (r = 0.55; P < .001) with the Adipose IR index was evident. Greater area under the curve FFAs (lower FFA suppression) during the OGTT was evident with worsening glucose tolerance (P for trend < .001). Glucose tolerance category, degree of obesity (body mass index–z score), IL-6, and low adiponectin emerged as significant predictors of the Adipose IR. CONCLUSIONS: Adipose IR is associated with reduced suppression of FFAs during the OGTT and with an altered adipocytokine profile. The negative relation with insulin secretion deserves further longitudinal investigation in the context of deteriorating glucose tolerance

Lower Insulin Clearance parallels a reduced insulin sensitivity in obese youths and is associated with a decline in \u3b2-cell function over time

We examined the relationship between insulin clearance, insulin sensitivity and \u3b2-cell function and the longitudinal effect of insulin clearance on \u3b2-cell function in lean, obese insulin sensitive and insulin resistant adolescents.A hyperinsulinemic-euglycemic and a hyperglycemic clamp were performed in 110 youths to quantify hepatic and peripheral clearance, insulin sensitivity and \u3b2-cell function (disposition index, DIh-clamp). Participants underwent an OGTT at baseline and after 2 years to assess glucose tolerance and oral \u3b2-cell function (oDIcpep) and were sorted into four groups (lean, obese NGT insulin sensitive and resistant, obese IGT). Insulin sensitivity was defined based on the median of insulin stimulated glucose disposal (M) measured during the hyperinsulinemic- euglyemic clamp.Lean and obese insulin sensitive participants did not differ with respect to hepatic and peripheral clearance, nor for insulin sensitivity. Insulin sensitivity was linearly correlated with whole body insulin clearance. Hepatic insulin extraction at baseline acted as independent determinant of \u3b2-cell function at follow-up.The decline in insulin sensitivity, even in the absence of an impairment of glucose tolerance, is associated with lowering of hepatic insulin clearance in obese youth, that in turn may contribute to the decline in \u3b2-Cell function over time

Metabolic and Genetic Determinants of Glucose Shape After Oral Challenge in Obese Youths : A Longitudinal Study

CONTEXT: The time-to-glucose-peak following the oral glucose tolerance test (OGTT) is a highly reproducible marker for diabetes risk. In obese youths, we lack evidence for the mechanisms underlying the effects of the TCF7L2 rs7903146 variant on glucose peak. METHODS: We analyzed the metabolic phenotype and the genotype for the TCF7L2 rs7903146 in 630 obese youths with normal (NGT) and impaired (IGT) glucose tolerance. Participants underwent a 3-hour, 9-point OGTT to estimate, using the oral minimal model, the disposition index (DI), the static (φstatic) and dynamic (φdynamic) components β-cell responsiveness and insulin sensitivity (SI). In a subgroup (n = 241) longitudinally followed for 2 years, we estimated the effect of time-to-glucose-peak on glucose tolerance change. RESULTS: Participants were grouped into early (<30 minutes) and late (≥30 minutes) glucose peakers. A delayed glucose peak was featured by a decline in φstatic (P < .001) in the absence of a difference in φdynamic. The prevalence of T-risk allele for TCF7L2 rs7903146 variant significantly increased in the late peak group. A lower DI was correlated with higher glucose concentration at 1 and 2 hours, whereas SI was inversely associated with 1-hour glucose. Glucose peak <30 minutes was protective toward worsening of glucose tolerance overtime (odds ratio 0.35 [0.15-0.82]; P = .015), with no subjects progressing to NGT or persisting IGT, in contrast to the 40% of progressor in those with late glucose peak. CONCLUSION: The prevalence of T-risk allele for the TCF7L2 rs7903146 prevailed in the late time-to-glucose peak group, which in turn is associated with impaired β-cell responsiveness to glucose (φ), thereby predisposing to prediabetes and diabetes in obese youths