Abstract— Overweight in childhood sets the stage for a lifelong struggle with weight and eating and raises the risk of health problems, such as obesity, diabetes mellitus, hypertension, sleep apnea, and heart disease. Research from multiple disciplinary fields has identified scores of contributing factors. Efforts to integrate these factors into a single “big picture” have been hampered by the challenges of constructing theoretical models that are both comprehensive and developmentally adaptable. This article reviews select genetic and environmental factors influencing childhood overweight and obesity, then explicates an ecological model mapping these and other factors. The Six‐Cs model extends previous theoretical work on childhood weight imbalance by acknowledging dimensions of factors specific to heredity as well as the environment, to activity as well as nutrition, to resources and opportunities as well as practices, and to development from birth through adolescence. This article concludes by discussing the model’s policy relevance and identifying important next steps for transdisciplinary research concerning child overweight and obesity.

The reduction in hepatic abundance of sterol regulatory element binding protein-1 (SREBP-1) mRNA and protein associated with the ingestion of polyunsaturated fatty acids (PUFA) appears to be largely responsible for the PUFA-dependent inhibition of lipogenic gene transcription. Our initial studies indicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA. Nuclear run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms. In this report we demonstrate that PUFA enhance the decay of both SREBP-1a and -1c. When rat hepatocytes in monolayer culture were treated with albumin-bound 20:4(n-6) or 20:5(n-3) the half-life of total SREBP-1 mRNA was reduced by 50%. Ribonuclease protection assays revealed that the decay of SREBP-1c mRNA was more sensitive to PUFA than was SREBP-1a, i.e. the half-life of SREBP-1c and -1a was reduced from 10.0 to 4.6 h and 11.6 to 7.6 h, respectively. Interestingly, treating the hepatocytes with the translational inhibitor, cycloheximide, prevented the PUFA-dependent decay of SREBP-1. This suggests that SREBP-1 mRNA may need to undergo translation to enter the decay process, or that the decay process requires the synthesis of a rapidly turning over protein. Although the mechanism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined, cloning and sequencing of the 3-untranslated region for the rat SREBP-1 transcript revealed the presence of an A-U-rich region that is characteristic of a destablizing element.Dietary (n-6) and (n-3) polyunsaturated fatty acids (PUFA) 1 lower blood triglycerides, decrease intra-muscular lipid droplet size, improve insulin sensitivity, and enhance nonhepatic glucose utilization (1-5). PUFA control these metabolic changes in two ways. First, they induce the transcription of genes encoding proteins involved in lipid oxidation, e.g. carnitine palmitoyltransferase (6) and acyl-CoA oxidase (7). Second, PUFA suppress the expression of genes encoding proteins involved in lipid synthesis, e.g. fatty acid synthase and acetyl-CoA carboxylase (8). Genes encoding the oxidative enzymes appear to be regulated by a common PUFA-activated transcription factor, peroxisome proliferator-activated receptor ␣ (9, 10). On the other hand, PUFA appear to coordinately inhibit hepatic lipogenic gene transcription by rapidly reducing the nuclear content of the lipogenic transcription factor, sterol regulatory element binding protein-1 (SREBP-1) (11-14).There are three members of the SREBP family: 1a, 1c, and 2 (15). SREBP-1 appears to be more involved with the regulation of lipogenic genes, while SREBP-2 may have the greatest influence on the expression of cholesterolgenic genes (16). The SREBPs were identified because of their ability to bind to the sterol regulatory element and confer sterol regulation to several genes involved with cholesterol synthesis (15). SREBPs are synthesized as 125-kDa precursor proteins that contain two transmembrane domains for insertion into the endoplasmic reticulum membrane (15). The N...

The beneficial effects of regular physical activity on insulin sensitivity (S I) and glucose tolerance are well documented, with considerable heterogeneity in responsiveness to exercise training (ET). To find novel candidate genes for ET-induced improvement in S I, we used microarray technology. Total RNA was isolated from vastus lateralis muscle before and after 20 wk of exercise from individuals participating in the HERITAGE Family Study. S I index was derived from a frequently sampled intravenous glucose tolerance test using MINMOD Millennium software. Sixteen subjects were selected: eight showing no changes in S I (low responders, LSIR) and eight displaying marked improvement in S I (high responders, HSIR) with ET. The SI increase was about four times greater in HSIR compared with LSIR (ϩ3.6 Ϯ 0.5 vs. Ϫ1.2 Ϯ 0.5 U⅐ml Ϫ1 ⅐min Ϫ1, mean Ϯ SE), whereas age, body mass index, percent body fat, and baseline SI were similar between the groups. Triplicate microarrays were performed, comparing pooled RNA with HS IR and LSIR individuals for differences in gene expression before and after ET using in situ-generated microarrays (18, 861 genes). Array data were validated by quantitative RT-PCR. Almost twice as many genes showed at least twofold differences between HS IR and LSIR after training compared with pretraining. We identified differentially expressed genes involved in energy metabolism and signaling, novel structural genes, and transcripts of unknown function. Genes of interest upregulated in HSIR include V-Ski oncogene, four-and-a-half LIM domain 1, and titin. Further study of these novel candidate genes should provide a better understanding of molecular mechanisms involved in the improvement in insulin sensitivity in response to regular exercise. microarray; MINMOD Millennium; exercise training

Refeeding carbohydrate to fasted rats induces the transcription of genes encoding enzymes of fatty acid biosynthesis, e.g. fatty-acid synthase (FAS). Part of this transcriptional induction is mediated by insulin. An insulin response element has been described for the fatty-acid synthase gene region of ؊600 to ؉65, but the 2-3-fold increase in fatty-acid synthase promoter activity attributable to this region is small compared with the 20 -30-fold induction in fatty-acid synthase gene transcription observed in fasted rats refed carbohydrate. We have previously reported that the fatty-acid synthase gene region between ؊7382 and ؊6970 was essential for achieving high in vivo rates of gene transcription. The studies of the current report demonstrate that the region of ؊7382 to ؊6970 of the fatty-acid synthase gene contains a carbohydrate response element (CHO-RE FAS ) with a palindrome sequence (CATGTGn 5 GGCGTG) that is nearly identical to the CHO-RE of the L-type pyruvate kinase and S 14 genes. The glucose responsiveness imparted by CHO-RE FAS was independent of insulin. Moreover, CHO-RE FAS conferred glucose responsiveness to a heterologous promoter (i.e. L-type pyruvate kinase). Electrophoretic mobility shift assays demonstrated that CHO-RE FAS readily bound a unique hepatic ChoRF and that CHO-RE FAS competed with the CHO-RE of the Ltype pyruvate kinase and S 14 genes for ChoRF binding. In vivo footprinting revealed that fasting reduced and refeeding increased ChoRF binding to CHO-RE FAS . Thus, carbohydrate responsiveness of rat liver fattyacid synthase appears to require both insulin and glucose signaling pathways. More importantly, a unique hepatic ChoRF has now been shown to recognize glucose responsive sequences that are common to three different genes: fatty-acid synthase, L-type pyruvate kinase, and S 14 .