Notch, a transmembrane receptor member of the homeotic epidermal growth factor-like family of proteins, participates in cell-to-cell signaling to control cell fate during development. Activated Notch-1 constructs lacking the extracellular region prevent differentiation of several mammalian cells in vitro. This effect, however, bypasses the normal mechanisms of cell-to-cell interactions in which Notch-1 participates. We investigated the role of Notch-1 in the hormone-induced adipocyte differentiation of 3T3-L1 fibroblasts, a paradigmatic model of adipogenesis that requires cell-to-cell contact. Unlike other differentiation models, Notch-1 expression and function were necessary conditions for adipogenesis. Impaired Notch-1 expression by antisense Notch-1 constructs prevented adipocyte differentiation. Strategies aimed at blocking putative Notch/ligand interactions also blocked adipogenesis, implicating Notch as a critical molecule in cell-to-cell signaling necessary for differentiation. Inhibition of Notch-1 expression or function decreased the expression of peroxisomal proliferatoractivated receptors ␦ and ␥, transcription factors that control adipocyte differentiation and that are up-regulated at cell confluence. These results implicate Notch in the commitment of 3T3-L1 cells to undergo adipogenesis by controlling the expression of the principal regulators of this process.

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Forty-two healthy men and women were subjected to four consecutive dietary periods differing in the fat content of saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (n-6) [PUFA(n-6)] and (n-3) [PUFA(n-3)]. Plasma lipids, vitamin E, and in vitro LDL oxidation were examined during each period. Adhesion of human monocytes to cultured human endothelial cells was used as a functional test to identify differences in the biological properties of LDL from each dietary period. Consumption of an SFA-rich diet resulted in higher LDL cholesterol (4.06 +/- 0.85 mmol/L, P < .05) than did consumption of MUFA- (3.59 +/- 0.75 mmol/L), PUFA(n-6)- (3.44 +/- 0.77 mmol/L), or PUFA(n-3)- (3.31 +/- 0.8 mmol/L) rich diets. HDL cholesterol was lower during both PUFA-rich diets (1.24 +/- 0.28 and 1.27 +/- 0.28 mmol/L for n-6 and n-3, respectively) than during the SFA-(1.32 +/- 0.36 mmol/L) and MUFA- (1.32 +/- 0.34 mmol/L) rich diets. LDL resistance to copper-induced oxidation, expressed as lag time, was highest during the MUFA-rich diet (55.1 +/- 7.3 minutes) and lowest during the PUFA(n-3)- (45.3 +/- 7 minutes) and SFA- (45.3 +/- 6.4 minutes) rich diets. LDL induction of monocyte adhesion to endothelial cells was lower during the MUFA-rich diet than the other periods. The highest monocyte adhesion was obtained during the PUFA(n-3) and SFA dietary periods. In conclusion, an MUFA-rich diet benefits plasma lipid levels compared with an SFA-rich diet. Furthermore, this diet results in an increased resistance of LDL to oxidation and a lower rate of monocyte adhesion to endothelial cells than the other dietary fats examined.

Development of diabetes generally re¯ects an inadequate mass of insulin-producing b-cells. b-cell proliferation and differentiation are regulated by a variety of growth factors and hormones, including insulin-like growth factor I (IGF-I). GRF1 is a Rasguanine nucleotide exchange factor known previously for its restricted expression in brain and its role in learning and memory. Here we demonstrate that GRF1 is also expressed in pancreatic islets. Interestingly, our GRF1-de®cient mice exhibit reduced body weight, hypoinsulinemia and glucose intolerance owing to a reduction of b-cells. Whereas insulin resistance is not detected in peripheral tissues, GRF1 knockout mice are leaner due to increased lipid catabolism. The reduction in circulating insulin does not re¯ect defective glucose sensing or insulin production but results from impaired b-cell proliferation and reduced neogenesis. IGF-I treatment of isolated islets from GRF1 knockouts fails to activate critical downstream signals such as Akt and Erk. The observed phenotype is similar to manifestations of preclinical type 2 diabetes. Thus, our observations demonstrate a novel and speci®c role for Ras-GRF1 pathways in the development and maintenance of normal b-cell number and function.

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The present study tests the hypothesis that higher consumption of bakery products, sweetened soft drinks and yogurt is associated with higher intake of energy, saturated fats, sugars and worse overall diet quality among Spanish children. This is a cross-sectional study covering 1112 children aged 6.0-7.0 years in four Spanish cities. Nutrient and food intake were obtained through a food-frequency questionnaire, and overall diet quality calculated using the healthyeating index (HEI) developed by Kennedy et al. (1995). Standardized methods were used to measure anthropometric variables. Associations of interest were summarized as the difference in nutrient and food consumption between the value of the fifth and the first quintile of consumption (dq) of bakery products, sweetened soft drinks or yogurt, adjusted for energy intake and BMI. Bakery products, sweetened soft drinks and yogurt supplied 15·5, 1·0 and 5·6 % energy intake respectively. Higher consumption of these three foods was associated with greater energy intake (P, 0·001), but not with higher BMI. Consumption of bakery products was associated with the proportion of energy derived from intake of total carbohydrates (dq 4·5 %, P, 0·001) and sugars (dq 2 %, P, 0·001), but did not show association with the HEI. Consumption of sweetened soft drinks was associated with a lower consumption of milk (dq 2 88 ml, P, 0·001) and Ca (dq 2 175 mg/d, P,0·001), and worse HEI (dq 22, P, 0·01). Consumption of yogurt, while associated with higher energy intake from saturated fats (dq 1·77 %, P, 0·001) and sugars (dq 2·02 %, P,0·001), showed no association with the HEI. Differences in the intake of nutrients and foods across quintiles of consumption of bakery products, sweetened soft drinks and yogurt were usually very small. We conclude that the impact of the consumption of bakery products, sweetened soft drinks and yogurt on the quality of the diet of Spanish children is only modest, although it may contribute to aggravating certain unhealthy characteristics of their diet, particularly excess energy, saturated fats and sugars. Therefore, consumption of bakery products and sweetened soft drinks should be moderated, and priority given to consumption of low-fat, low-sugar yogurt. Abbreviations: dq, value of the fifth minus the first quintile of consumption; FFQ, food-frequency questionnaire; HEI, healthy-eating index.

Objective: Classic cardiovascular risk factors, such as smoking, arterial hypertension and hypercholesterolaemia, cannot explain a substantial part of the geographic differences in cardiovascular mortality. Anthropometric and nutritional factors in early stages of life may contribute to adult cardiovascular disease. Therefore, this work examines certain anthropometric variables and diet among children aged 6 -7 y, living in four Spanish cities with widely differing ischaemic heart disease (IHD) mortality. Design and setting: Cross-sectional anthropometric and dietary survey in four cities in Spain. Subjects: A total of 1112 children (50.1% males, 49.9% females) attending public and private schools in Cadiz and Murcia, cities with a relatively high IHD mortality, and Madrid and Orense, cities with a relatively low IHD mortality. A standardized method was used to measure anthropometric variables, and a food-frequency questionnaire completed by subjects' mothers, to measure diet. Outcome measures: Body mass index (BMI), overweight (BMI > 17.6 kg=m 2 ), obesity (BMI > 20.1 kg=m 2 ) and intake of food and nutrients. Results: Children in the four cities showed a high prevalence of overweight (range across cities, 28.9 -34.5%) and obesity (8.5 -15.7%). They also had a moderately hypercaloric diet (range, 2078 -2218 kcal=day), marked by an excessive intake of lipids (45.0 -47.3% kcal), particularly saturated fats (16.6 -16.9% kcal), proteins (17.0 -17.3% kcal), sugars (20.0 -21.9% kcal) and cholesterol (161.6 -182.9 mg=1000 kcal=day), and a low intake of complex carbohydrates (17.5 -18.1% kcal) and fibre (19.6 -19.9 g=day). Compared with children in the two low-IHD-mortality cities, those in the two high-IHD-mortality cities had a greater BMI (mean difference, 0.61 kg=m 2 ; P ¼ 0.0001) and ponderal index (0.58 kg=m 3 ; P ¼ 0.0001) and a higher intake of energy (104 kcal=day; P ¼ 0.007), cholesterol (16.00 mg=1000 kcal=day; P ¼ 0.0001) and sodium (321 mg=day; P ¼ 0.0001). Inter-city differences in anthropometric variables remained after adjustment for birthweight. Conclusions: Intake of fats, especially saturated fats, and cholesterol should be reduced among Spanish children. It could contribute to a needed reduction of the high prevalence of overweight and obesity in children. If the differences in anthropometric variables and diet between children from the cities with high and low coronary mortality are maintained in future or continue into adulthood, this could contribute to consolidate or even increase the IHD mortality gradient across cities. The finding that differences in anthropometric variables are independent of birthweight suggests that the childhood, rather than intrauterine environment, is involved in the development of such differences.

Objective: To compare the diet of Spanish children against the nutrient and food intake guidelines. To calculate an index of overall diet quality and check its validity against nutrient intake. Design and setting: Cross-sectional study in four cities in Spain, where information on food and nutrient intake was obtained from schoolchildren through a food frequency questionnaire. Participants: The sample included 1112 children (overall response rate of 85%) attending public and private schools and aged 6-7 y. Children were selected through random cluster sampling in schools, and stratified by sex and socioeconomic level. Main Outcome Measures: Mean nutrient intake, number of food servings, and the percentage of children who meet recommended nutrient and food-serving intake levels. The overall dietary quality was assessed using the Healthy Eating Index (HEI). Results: Mean micronutrient intake exceeded 100% of the recommended dietary allowances, except for vitamin B6, which registered a mean intake of 77.1%. For almost all children, intake of saturated fat was above, and that of carbohydrate below, the recommended level, in contrast to the relatively high compliance with the recommendations for poly-and monounsaturated fatty acid, salt and fiber intake (69.7, 43.7, 40.7, and 30.1%, respectively). Consumption of food servings for each of the five American pyramid food groups came close to or exceeded USDA guidelines, with the exception of cereals, with 5.4 servings per day. The mean score obtained in the HEI was 64.6. Children who complied with all the food guide pyramid recommendations registered a higher dietary variety and a healthier nutritional profile. Conclusions: Children aged 6-7 y show scant compliance with the macronutrient goals for healthy eating. Micronutrient intake is adequate in general, yet there are small groups of children with risk of deficient intake of vitamins B6 and D. While Spanish children's eating habits are reasonably in line with American food guide pyramid guidelines, consumptions of cereals and fruit should be improved.