SaludABLEOmaha: improving readiness to address obesity through healthy lifestyle in a Midwestern Latino community, 2011-2013.

BACKGROUND: A community's readiness for change is a precursor to the effective application of evidence-based practices for health promotion. Research is lacking regarding potential strategies to improve readiness to address obesity-related health issues in underserved communities. COMMUNITY CONTEXT: This case study describes SaludABLEOmaha, an initiative to increase readiness of residents in a Midwestern Latino community to address obesity and adopt healthy lifestyles. METHODS: SaludABLEOmaha emphasized 2 core approaches, youth activism and collaboration among public and private institutions, which we applied to planning and implementing tactics in support of 3 interconnected strategies: 1) social marketing and social media, 2) service learning in schools (ie, curricula that integrate hands-on community service with instruction and reflection), and 3) community and business engagement. Following the Community Readiness Model protocol (http://triethniccenter.colostate.edu/communityReadiness.htm), structured interviews were conducted with community leaders and analyzed before and 2.5 years after launch of the program. OUTCOME: The community increased in readiness from stage 3 of the Community Readiness Model, "vague awareness," at baseline to stage 5, "preparation," at follow-up. INTERPRETATION: SaludABLEOmaha improved community readiness (eg, community knowledge, community climate), which probably contributed to the observed increase in readiness to address obesity through healthy lifestyle. Community mobilization approaches such as youth activism integrated with social marketing and social media tactics can improve community responsiveness to obesity prevention and diminish health disparities.

Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats.

Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg(-1)·h(-1))] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg(-1)·h(-1)) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats.

The Synergistic Effect of an ATP-Competitive Inhibitor of mTOR and Metformin on Pancreatic Tumor Growth.

BACKGROUND: The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing pathway and a key regulator of amino acid and glucose metabolism. Dysregulation of the mTOR pathways is implicated in the pathogenesis of metabolic syndrome, obesity, type 2 diabetes, and pancreatic cancer. OBJECTIVES: We investigated the impact of inhibition of mTORC1/mTORC2 and synergism with metformin on pancreatic tumor growth and metabolomics. METHODS: Cell lines derived from pancreatic tumors of the KPC (KrasG12D/+; p53R172H/+; Pdx1-Cre) transgenic mice model were implanted into the pancreas of C57BL/6 albino mice (n = 10/group). Two weeks later, the mice were injected intraperitoneally with daily doses of 1) Torin 2 (mTORC1/mTORC2 inhibitor) at a high concentration (TH), 2) Torin 2 at a low concentration (TL), 3) metformin at a low concentration (ML), 4) a combination of Torin 2 and metformin at low concentrations (TLML), or 5) DMSO vehicle (control) for 12 d. Tissues and blood samples were collected for targeted xenometabolomics analysis, drug concentration, and cell signaling. RESULTS: Metabolomic analysis of the control and treated plasma samples showed differential metabolite profiles. Phenylalanine was significantly elevated in the TLML group compared with the control (+426%, P = 0.0004), whereas uracil was significantly lower (-38%, P = 0.009). The combination treatment reduced tumor growth in the orthotopic mouse model. TLML significantly decreased pancreatic tumor volume (498 ± 104 mm3; 37%; P < 0.0004) compared with control (1326 ± 134 mm3; 100%), ML (853 ± 67 mm3; 64%), TL (745 ± 167 mm3; 54%), and TH (665 ± 182 mm3; 50%) (ANOVA and post hoc tests). TLML significantly decreased tumor weights (0.66 ± 0.08 g; 52%) compared with the control (1.28 ± 0.19 g; 100%) (P < 0.002). CONCLUSIONS: The combination of mTOR dual inhibition by Torin 2 and metformin is associated with an altered metabolomic profile and a significant reduction in pancreatic tumor burden compared with single-agent therapy, and it is better tolerated.

Assessing the validity and reliability of family factors on physical activity: A case study in Turkey.

BACKGROUND: Childhood obesity rates have been rising rapidly in developing countries. A better understanding of the risk factors and social context is necessary to inform public health interventions and policies. This paper describes the validation of several measurement scales for use in Turkey, which relate to child and parent perceptions of physical activity (PA) and enablers and barriers of physical activity in the home environment. METHOD: The aim of this study was to assess the validity and reliability of several measurement scales in Turkey using a population sample across three socio-economic strata in the Turkish capital, Ankara. Surveys were conducted in Grade 4 children (mean age = 9.7 years for boys; 9.9 years for girls), and their parents, across 6 randomly selected schools, stratified by SES (n = 641 students, 483 parents). Construct validity of the scales was evaluated through exploratory and confirmatory factor analysis. Internal consistency of scales and test-retest reliability were assessed by Cronbach's alpha and intra-class correlation. RESULTS: The scales as a whole were found to have acceptable-to-good model fit statistics (PA Barriers: RMSEA = 0.076, SRMR = 0.0577, AGFI = 0.901; PA Outcome Expectancies: RMSEA = 0.054, SRMR = 0.0545, AGFI = 0.916, and PA Home Environment: RMSEA = 0.038, SRMR = 0.0233, AGFI = 0.976). The PA Barriers subscales showed good internal consistency and poor to fair test-retest reliability (personal α = 0.79, ICC = 0.29, environmental α = 0.73, ICC = 0.59). The PA Outcome Expectancies subscales showed good internal consistency and test-retest reliability (negative α = 0.77, ICC = 0.56; positive α = 0.74, ICC = 0.49). Only the PA Home Environment subscale on support for PA was validated in the final confirmatory model; it showed moderate internal consistency and test-retest reliability (α = 0.61, ICC = 0.48). DISCUSSION: This study is the first to validate measures of perceptions of physical activity and the physical activity home environment in Turkey. Our results support the originally hypothesized two-factor structures for Physical Activity Barriers and Physical Activity Outcome Expectancies. However, we found the one-factor rather than two-factor structure for Physical Activity Home Environment had the best model fit. This study provides general support for the use of these scales in Turkey in terms of validity, but test-retest reliability warrants further research.

Effects of Metformin and a Mammalian Target of Rapamycin (mTOR) ATP-Competitive Inhibitor on Targeted Metabolomics in Pancreatic Cancer Cell Line.

Pancreatic Cancer (PC) is a devastating lethal disease. Therefore, there is an urgent need to develop new intervention strategies. The mammalian Target of Rapamycin (mTOR) is a conserved kinase and master regulator of metabolism and cell growth. mTOR is dysregulated in chronic diseases including diabetes and pancreatic cancer. Recent reports indicate that 50% of Pancreatic Ductal Adenocarcinoma (PDAC) patients are diabetic at the time of diagnosis. Furthermore, the anti-diabetic drug, metformin, which indirectly inhibits mTOR, has emerged as a potential therapeutic target for PC. The objective of this study is to determine the targeted-metabolomics profile in PDAC cell line (HPAF-II) with mTOR inhibition and the interaction between mTOR ATP-competitive inhibitor (Torin 2) and metformin as potential combined therapy in PC. HPAF-II cell lines were cultured in the presence of either Torin 2, metformin, both, or control vehicle. We utilized targeted LC/MS/MS to characterize the alterations in glycolytic and tricarboxylic acid cycle metabolomics, and employed Western Blot analysis for cell signaling activation by phosphorylation. Comparisons between groups were analyzed using one-way Analysis of Variance followed by secondary post-hoc analysis. After 1 h incubation with metformin, AMP concentration was significantly increased compared to other groups (p<0.03). After 24 h, Torin-2 significantly decreased glycolysis intermediates (fructose 1,6-bisphosphate (FBP), and 2-phosphoglycerate/3-phosphoglycerate), TCA intermediate metabolites (citrate/isocitrate, and malate), as well as Nicotinamide Adenine Dinucleotide (NAD+) and Flavin Adenine Dinucleotide (FAD), and ATP levels. When HPAF-II cells were incubated with both Torin-2 and metformin, there was a significant reduction in NAD+ and FAD, suggesting decreased levels of the energy equivalents that are available to the electron transport chain. Targeted metabolomics data indicate that mTOR complexes inhibition by Torin 2 reduced glycolytic intermediates and TCA metabolites in HPAF- II and may synergize with metformin to decrease the electron acceptors NAD+ and FAD which may lead to reduced energy production.

Effects of exendin-4 alone and with peptide YY(3-36) on food intake and body weight in diet-induced obese rats.

Significant weight loss following Roux-en-Y gastric bypass surgery (RYGB) in obese humans correlates with enhanced secretion of anorexigenic gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY(3-36) (PYY(3-36)). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP-1 homologue exendin-4 alone and with PYY(3-36) that produces a sustained reduction in daily food intake and body weight in diet-induced obese (DIO) rats. We tested 12 exendin-4 strategies over 10 weeks. Exendin-4 infused during the first and last 3 h of the dark period at 15-20 pmol/h (0.15 nmol/kg/day) produced a sustained 24 ± 1% reduction in daily food intake for 17 days, and decreased body weight by 7%. In a separate group of DIO rats, none of seven dosing strategies combining exendin-4 and PYY(3-36) produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin-4 alone and with PYY(3-36) on food intake and body weight in each experiment suggested possible receptor downregulation and tolerance to treatments. However, when treatments were discontinued for 1 day following losses in efficacies, daily food intake significantly increased. Together, these results demonstrate that (i) intermittent IP infusion of a low dose of exendin-4 can produce a relatively prolonged reduction in daily food intake and body weight in DIO rats, (ii) co-infusion of exendin-4 and PYY(3-36) does not further prolong this response, and (iii) activation of an orexigenic mechanism gradually occurs to counteract the inhibitory effects of exendin-4 alone and with PYY(3-36) on food intake and body weight.