👤 Sonia Caprio

Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae. Eight hundred seventy-seven youth (6-21 years) with overweight/obesity, recruited from the Yale Pediatric Obesity Clinic in New Haven, CT, underwent genetic analysis to screen for functionally damaging, rare variants (MAF < 0.01) in MC4R. Participants were assigned to a Pathogenic Variant or No Pathogenic Variant group and completed a 10-timepoint 180-min oral glucose tolerance test (OGTT) and abdominal MRI. Compared to the No Pathogenic Variant group, the Pathogenic Variant group demonstrated significantly greater glucose concentrations (AUC Pathogenic variants in MC4R are associated with increased VAT, HFF%, and insulin resistance, independent from the degree of obesity in youth. Show less

Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood. To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study. We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait. We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance ( Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D. Show less

Dual specificity mitogen-activated protein kinase (MAPK) phosphatases [dual specificity phosphatase/MAP kinase phosphatase (DUSP-MKP)] have been hypothesized to maintain cancer cell survival by buffering excessive MAPK signaling caused by upstream activating oncogenic products. A large and diverse body of literature suggests that genetic depletion of DUSP-MKPs can reduce tumorigenicity, suggesting that hyperactivating MAPK signaling by DUSP-MKP inhibitors could be a novel strategy to selectively affect the transformed phenotype. Through in vivo structure-activity relationship studies in transgenic zebrafish we recently identified a hyperactivator of fibroblast growth factor signaling [(E)-2-benzylidene-5-bromo-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI-215)] that is devoid of developmental toxicity and restores defective MAPK activity caused by overexpression of DUSP1 and DUSP6 in mammalian cells. Here, we hypothesized that BCI-215 could selectively affect survival of transformed cells. In MDA-MB-231 human breast cancer cells, BCI-215 inhibited cell motility, caused apoptosis but not primary necrosis, and sensitized cells to lymphokine-activated killer cell activity. Mechanistically, BCI-215 induced rapid and sustained phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) in the absence of reactive oxygen species, and its toxicity was partially rescued by inhibition of p38 but not JNK or ERK. BCI-215 also hyperactivated MKK4/SEK1, suggesting activation of stress responses. Kinase phosphorylation profiling documented BCI-215 selectively activated MAPKs and their downstream substrates, but not receptor tyrosine kinases, SRC family kinases, AKT, mTOR, or DNA damage pathways. Our findings support the hypothesis that BCI-215 causes selective cancer cell cytotoxicity in part through non-redox-mediated activation of MAPK signaling, and the findings also identify an intersection with immune cell killing that is worthy of further exploration. Show less

Insulin resistance associated with altered fat partitioning in liver and adipose tissues is a prediabetic condition in obese adolescents. We investigated interactions between glucose tolerance, insulin sensitivity, and the expression of lipogenic genes in abdominal subcutaneous adipose and liver tissue in 53 obese adolescents. Based on their 2-h glucose tests they were stratified in the following groups: group 1, 2-h glucose level <120 mg/dL; group 2, 2-h glucose level between 120 and 140 mg/dL; and group 3, 2-h glucose level >140 mg/dL. Liver and adipose tissue insulin sensitivity were greater in group 1 than in group 2 and group 3, and muscle insulin sensitivity progressively decreased from group 1 to group 3. The expression of the carbohydrate-responsive element-binding protein (ChREBP) was decreased in adipose tissue but increased in the liver (eight subjects) in adolescents with impaired glucose tolerance or type 2 diabetes. The expression of adipose ChREBPα and ChREBPβ was inversely related to 2-h glucose level and positively correlated to insulin sensitivity. Improvement of glucose tolerance in four subjects was associated with an increase of ChREBP/GLUT4 expression in the adipose tissue. In conclusion, early in the development of prediabetes/type 2 diabetes in youth, ChREBPβ expression in adipose tissue predicts insulin resistance and, therefore, might play a role in the regulation of glucose tolerance. Show less

Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3, but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians (P = 0.00161), 39.0% in African Americans (P = 0.00000496), and 15% in Hispanics (P = 0.00342). The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths. Show less