This proposal seeks support for a long-standing translational grant funded continuously by NICHD for the past 22 years, serving as the primary vehicle for work investigating the pathogenesis of IR in adolescent obesity. We described a distinct endophenotype in obese adolescents characterized by a thin superficial layer of abdominal subcutaneous adipose tissue (SAT), increased visceral adipose tissue (VAT), marked IR, dyslipidemia, and fatty liver. During the last cycle of the grant, we began to unravel the cellular/molecular mechanisms associated with this phenotype and its relations to IR. We demonstrated a key role of impaired subcutaneous abdominal adipogenesis in the pathogenesis of IR in obese adolescents supporting the hypothesis that the ability to retain fat in the subcutaneous depots seems to be associated with decreased VAT and reduced ectopic fat deposition and a more favorable metabolic profile. Building on these findings we propose 3 major hypotheses: Hypothesis 1: The reduced transcription of key lipogenic/adipogenic genes in abd SAT translates into reduced in vivo TG synthesis and adipocyte proliferation, which in turn will contribute to ectopic fat accumulation and IR in obese adolescents with a High VAT/SAT ratio. Hypothesis 2: The storage capacity of gluteal SAT is a determinant for the level of VAT/SAT fat distribution in obese adolescents. Approach for Hypothesis 1 & 2: We will employ the novel method of 2H2O to quantify in vivo TG synthesis, and adipocyte proliferation. This method will be added to measures of adipocyte size distribution, gene expression, regional fat distribution (MRI & DEXA) and clamp measures of insulin sensitivity in obese adolescents with a high VAT/SAT ratio compared to an age, gender and pubertal stage matched group with a low VAT/SAT ratio. Hypothesis 3A: High dietary intake of palmitate is associated with an increased ceramide content which in turn might upregulate the inflammasome complex in the SAT thereby contributing to IR in obese adolescents. Hypothesis 3B: To explore if reducing the dietary intake of palmitate will decrease the production of ceramide in the SAT which will mitigate the activation of the inflammasome complex and reduce IR in obese adolescents with a High VAT/SAT ratio. Approach for Hypothesis 3A&3B: The plasma and SAT (abd & gluteal) sphingolipid concentrations will be determined by LC-MS/MS, by Dr. Scherer at UTSW and related to the intake of palmitate intake obtained by a three day dietary intake. Activation of caspase-1 protein will be measured by western blot (Dr. Dixit's lab at Yale) and transcriptomic of regulatory genes of caspase-1 by qPCR, which will be measured before and after two months of a randomized parallel control study with a low palmitate/saturated fat dietary intervention. The studies outlined here will provide a better understanding of IR in adolescent obesity. The grant will accomplish these aims through unifying a collaborative interdisciplinary team of world-renowned scientists at Yale spanning the breadth of disciplines from clinical sciences (Pediatrics) to basic sciences (Immunology, Adipose biology) to Nutritional Sciences (UC Berkeley and UVM).
Insulin Resistance is the best predictor of whether the obese adolescent will develop type 2 diabetes and, though it affects a large number of obese adolescents worldwide, its pathogenesis remains elusive. Our previous studies clearly established the link between the impaired accumulation of fat in abdominal subcutaneous depot, fatty liver and peripheral insulin resistance in obese adolescents. The present continuation studies will focus on determining what might cause the lack of fat to accumulate in the subcutaneous fat regions and lead to local inflammation, causing a perfect storm of insulin resistance to develop in obese adolescents.
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|Weiss, Ram; Santoro, Nicola; Giannini, Cosimo et al. (2017) Prediabetes in youth - mechanisms and biomarkers. Lancet Child Adolesc Health 1:240-248|
|Goffredo, Martina; Santoro, Nicola; Tricò, Domenico et al. (2017) A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients 9:|
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|Tricò, Domenico; Di Sessa, Anna; Caprio, Sonia et al. (2017) Oxidized Derivatives of Linoleic Acid in Pediatric Metabolic Syndrome: Is Their Pathogenic Role Modulated by the Genetic Background and the Gut Microbiota? Antioxid Redox Signal :|
|Cropano, Catrina; Santoro, Nicola; Groop, Leif et al. (2017) The rs7903146 Variant in the TCF7L2 Gene Increases the Risk of Prediabetes/Type 2 Diabetes in Obese Adolescents by Impairing ?-Cell Function and Hepatic Insulin Sensitivity. Diabetes Care 40:1082-1089|
|Goffredo, Martina; Caprio, Sonia; Feldstein, Ariel E et al. (2016) Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology 63:117-25|
|Skeldon, Alexander M; Morizot, Alexandre; Douglas, Todd et al. (2016) Caspase-12, but Not Caspase-11, Inhibits Obesity and Insulin Resistance. J Immunol 196:437-47|
|Hershkop, Karen; Besor, Omri; Santoro, Nicola et al. (2016) Adipose Insulin Resistance in Obese Adolescents Across the Spectrum of Glucose Tolerance. J Clin Endocrinol Metab 101:2423-31|
|Garcia-Martinez, Irma; Santoro, Nicola; Chen, Yonglin et al. (2016) Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest 126:859-64|
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