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 .

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Dietary PUFAs (polyunsaturated fatty acids) co-ordinately suppress transcription of a group of hepatic genes encoding glycolytic and lipogenic enzymes. Suppression of Fasn (fatty acid synthase) transcription involves two PUFA-responsive regions, but the majority of PUFA sensitivity maps to a region within the proximal promoter containing binding sites for NF-Y (nuclear factor-Y), Sp1 (stimulatory protein 1), SREBP (sterol-regulatory-elementbinding protein), and USF (upstream stimulatory factor). Promoter activation assays indicate that altered NF-Y is the key component in regulation of Fasn promoter activity by PUFA. Using electrophoretic mobility-shift assay and chromatin immunoprecipitation analysis, we demonstrate for the first time that PUFAs decrease in vivo binding of NF-Y and SREBP-1c to the proximal promoter of the hepatic Fasn gene and the promoters of three additional genes, spot 14, stearoyl-CoA desaturase and farnesyl diphosphate synthase that are also down-regulated by PUFA. The comparable 50% decrease in NF-Y and SREBP-1c binding to the promoters of the respective PUFA-sensitive genes occurred despite no change in nuclear NF-Y content and a 4-fold decrease in SREBP-1c. Together, these findings support a mechanism whereby PUFA reciprocally regulates the binding of NF-Y and SREBP-1c to a subset of genes which share similar contiguous arrangements of sterol regulatory elements and NF-Y response elements within their promoters. PUFA-dependent regulation of SREBP-1c and NF-Y binding to this unique configuration of response elements may represent a nutrient-sensitive motif through which PUFA selectively and co-ordinately targets subsets of hepatic genes involved in lipid metabolism.

It is still not possible to provide an evidence-based answer to the question of whether regular exercise is essential for normal growth. It is also unclear whether very low levels of exercise result in growth deficits. Regular exposure to exercise is characterized by heterogeneity in responsiveness, with most individuals experiencing improvements in fitness traits but a significant proportion showing only very minor gains. Whether a sedentary mode of life during the growing years results in a permanent deficit in cardiorespiratory fitness or a diminished ability to respond favorably to regular exercise later in life remains to be investigated. Although several genes have been associated with fitness levels or response to regular exercise, the quality of the evidence is weak mainly because studies are statistically underpowered. The special case of the obese, sedentary child is discussed, and the importance of the "energy gap" in the excess weight gain during growth is highlighted. Obese, sedentary children have high blood pressure, dyslipidemia, elevated glycemia and type 2 diabetes, hepatic steatosis, respiratory problems, orthopedic complications, and other health disorders more frequently than normal weight, physically active children. The role of genetic differences in the inclination to be sedentary or physically active is reviewed. An understanding of the true role of genetic differences and regular exercise on the growth of children will require more elaborate paradigms incorporating not only DNA sequence variants and exercise exposure but also information on nutrition, programming, and epigenetic events during fetal life and early postnatal years.

The fat mass (FM) and obesity‐associated (FTO) gene is the first obesity‐susceptibility gene identified by genome‐wide association scans and confirmed in several follow‐up studies. Homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele. However, it is not known whether regular exercise‐induced changes in body composition are influenced by the FTO genotype. The purpose of our study was to test whether the FTO genotype is associated with exercise‐induced changes in adiposity. Body composition was derived from underwater weighing before and after a 20‐week endurance training program in 481 previously sedentary white subjects of the HERITAGE Family Study. FTO single‐nucleotide polymorphism (SNP) rs8050136 was genotyped using Illumina GoldenGate assay. In the sedentary state, the A/A homozygotes were significantly heavier and fatter than the heterozygotes and the C/C homozygotes in men (P = 0.004) but not in women (P = 0.331; gene‐by‐sex interaction P = 0.0053). The FTO genotype was associated with body fat responses to regular exercise (P < 0.005; adjusted for age, sex, and baseline value of response trait): carriers of the C allele showed three times greater FM and %body fat losses than the A/A homozygotes. The FTO genotype explained 2% of the variance in adiposity changes. Our data suggest that the FTO obesity‐susceptibility genotype influences the body fat responses to regular exercise. Resistance to exercise‐induced reduction in total adiposity may represent one mechanism by which the FTO A allele promotes overweight and obesity.