BackgroundA 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 ContextThis case study describes SaludABLEOmaha, an initiative to increase readiness of residents in a Midwestern Latino community to address obesity and adopt healthy lifestyles.MethodsSaludABLEOmaha 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. OutcomeThe community increased in readiness from stage 3 of the Community Readiness Model, “vague awareness,” at baseline to stage 5, “preparation,” at follow-up.InterpretationSaludABLEOmaha 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.

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 YY3–36 (PYY3–36). Our aim here was to identify a dosing strategy for intraperitoneal (IP) infusion of GLP‐1 homologue exendin‐4 alone and with PYY3–36 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 PYY3–36 produced a similar reduction in daily food intake for >10 days. The subsequent decline in efficacies of exendin‐4 alone and with PYY3–36 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 PYY3–36 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 PYY3–36 on food intake and body weight.

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 leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats. Am J Physiol Endocrinol Metab 302: E1576 -E1585, 2012. First published April 17, 2012; doi:10.1152/ajpendo.00058.2012.-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 Ϫ1 ·h Ϫ1 )] 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 Ϫ1 ·h Ϫ1 ) 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. food restriction; hyperphagia; leptin sensitivity; glucagon-like peptide-1 receptor agonist OBESITY IS A CHRONIC, stigmatized, and costly disease that is rarely curable and is increasing in prevalence in most of the world (4). Current therapies for producing weight loss in obese individuals, i.e., dieting, exercise, and medications, are woefully ineffective in producing long-term weight loss. This is likely due to redundancy and plasticity in the complex physiological system that controls food intake and regulates energy reserves. Many experts believe that multidrug therapy aimed at different components of this regulatory system will be required to produce a significant reduction in adiposity (4,13,21,22).An important early step in the development of antiobesity drugs is determining whether chronic administration of anorexigenic substances, alone or in combination, can produce a prolonged decrease in daily food intake and adiposity in experimental animals. Methods of administration usually include daily injections or insertion of an osmotic minipump beneath the skin or into the peritoneal cavity to deliver substances continuously for 1 wk...

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. Objective 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 surgically implanted into the pancreas of C57BL/6 albino mice (n = 10/group). Two weeks later, the mice were injected intraperitoneally (IP) 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 days. 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), while 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 &lt; 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 (0.66 ± 0.08 gm; 52%) tumor weights compared with the control (1.28± 0.19 gm; 100%) [p &lt; 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 to single-agent therapy, and is better tolerated. We investigated a nutrient-sensing pathway, mTORC1/mTORC2, inhibition, and synergism with metformin on pancreatic tumor metabolism. Combined treatment showed a differential metabolomics profile and a reduction in pancreatic tumor size and weight.