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The leptin signaling cascade and pediatric obesity
682
Abstracts / Appetite 54 (2010) 631–683
Exercise vs. enriched environment. Effects on obesity in male and female OLETF rats A. WELLER ∗ , M. SCHROEDER, L. SHBIRO Bar-Ilan University, RamatGan, Israel OLETF rats lack CCK1 receptors and are a model of early onset hyperphagia-induced obesity. They show pre-obese characteristics from birth, becoming gradually obese towards adolescence. We evaluated the post-weaning environment’s contribution to their obese phenotype by (1) providing obese and lean (LETO) strain males and females with running wheels for 3 weeks postweaning. (2) Chronic group housing with large cages and toy—an enriched environment (EE). Body weight (BW), voluntary intake, adiposity, leptin, insulin, corticosterone and adiponectin levels were among the parameters examined at adulthood. The results suggest a significant contribution of the rearing conditions to the OLETF males’ hyperphagia and obesity. Intake was reduced similarly after RW and EE (around 15%), while BW reduction was around 8% and 1.5%, respectively. RW OLETF males reduced 32% retroperitoneal and inguinal fat and 39% visceral fat, while after EE the reduction was 21% and 13% respectively. Accordingly, leptin levels were reduced 33% after RW vs. 18% after EE. In contrast, OLETF females adhered to their genotype, presenting strong resistance to adiposity loss after both manipulations, with no evident beneficial responses. Male LETO responded to exercise by reducing intake and adiposity levels while females increased intake, BW and muscle mass. Enriched environment had no effect on LETO physiology. Overall, the moderation in adiposity observed after EE and RW in the OLETF males suggests that standard, impoverished conditions may exacerbate the hyperphagia and obesity of the males, worsening their phenotype. doi:10.1016/j.appet.2010.04.210
Psychosocial influence on diet preference and caloric intake in female monkeys M.E. WILSON ∗ , V. MICHOPOULOS Emory University, Atlanta, GA, USA Social dominance status in macaque monkeys functions to control aggression and access to resources. Because subordination is imposed through non-contact aggression, the continual harassment of subordinate females by more dominant animals emerges as a potent psychosocial stressor, resulting in periodic hypercortisolemia, less frequent targets of affiliative behavior, and increased anxiety behaviors, associated with changes in monoamine activity in limbic-hypothalamic regions. Social status differences are also evident in appetite and energy regulation. When fed a low fat high fiber diet, subordinates eat less, reflected in fewer and smaller meals, have lower body weight, less total body fat, and a hypometabolic condition. However, estimates of energy expenditure, assessed from activity patterns, do not show a social status difference. In contrast, when given a choice between this low caloric diet (LCD) and diet high in fat and sugar, subordinates consume significantly more calories, largely from the high caloric diet (HCD). While dominant females also prefer the HCD, they nonetheless show caloric restriction, consuming similar calories regardless of diet availability. Although stress hormone responsivity is not affected, the increased consumption of the HCD is anxiolytic in subordinate females whereas the removal of the HCD is anxiogenic in all females. The model provides the opportunity to examine the neurobiological mechanisms for understanding the comorbidity of anxiety and emotional feeding in females. Supported by NIH HD46501, F32-MH073525, RR00165 and NFS IBN 9876754. doi:10.1016/j.appet.2010.04.211
The leptin signaling cascade and pediatric obesity J.A. YANOVSKI National Institutes of Health, Bethesda, MD, USA The prevalence of overweight and obesity in children has tripled during the past 40 years. This alarming rise in body weight has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this environment has not led to severe obesity in all children; rather, it has unmasked a select group of individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorie/low activity environment. This presentation will review inactivating mutations in the leptin signaling cascade that are associated with pediatriconset obesity and present some of the translational studies that have attempted treatment directed at correcting the observed defects. doi:10.1016/j.appet.2010.04.212
Anti-angiotensin type 1 receptor siRNA delivered into rat hypothalamus. A traceable reagent that reduces angiotensin binding, signal transduction and thirst D.K. YEE ∗ , L.A. FELGENDREDER, L.M. FLANAGAN-CATO University of Pennsylvania, Philadelphia, PA, USA Angiotensin II (AngII) is involved in the control of water and salt intake. Traditional approaches to study the cellular mechanisms that underlie these behaviors have relied on receptor ligands and other inhibitors injected into rat hypothalamus. These reagents have limitations: the extent of their diffusion in the brain is unknown and specific inhibitors are not available for many potential targets. Thus, we injected siRNA into rat brain targeting the AngII type 1 receptor (AT1R) as a platform to optimize procedures for other effective siRNA-mediated selective protein knockdown. First, we used an in vitro model (WB cells) to evaluate various AT1R siRNA sequence candidates. One siRNA candidate diminished AT1R levels by 90% and blocked any AngII-induced cell signaling compared to cells pretreated with luciferase (nonsilencing) siRNA. With the efficacy of an AT1R siRNA validated in WB cells, we began using this siRNA in vivo. Preliminary results have shown that rats treated with a single icv injection of AT1R siRNA substantially reduced their drinking responses to subsequent AngII injections compared to non-silencing siRNA at 22 h and 46 h. Furthermore, preliminary radioligand binding assays of the hypothalami of siRNA-treated rats demonstrated that AT1R siRNA diminished AT1R binding activity compared to the non-silencing siRNA. Experiments using biotin-tagged siRNAs are now planned to determine the extent of the affected areas by these reagents. Supported by NHLBI HL091314. doi:10.1016/j.appet.2010.04.213
Abstracts / Appetite 54 (2010) 631–683
Exercise vs. enriched environment. Effects on obesity in male and female OLETF rats A. WELLER ∗ , M. SCHROEDER, L. SHBIRO Bar-Ilan University, RamatGan, Israel OLETF rats lack CCK1 receptors and are a model of early onset hyperphagia-induced obesity. They show pre-obese characteristics from birth, becoming gradually obese towards adolescence. We evaluated the post-weaning environment’s contribution to their obese phenotype by (1) providing obese and lean (LETO) strain males and females with running wheels for 3 weeks postweaning. (2) Chronic group housing with large cages and toy—an enriched environment (EE). Body weight (BW), voluntary intake, adiposity, leptin, insulin, corticosterone and adiponectin levels were among the parameters examined at adulthood. The results suggest a significant contribution of the rearing conditions to the OLETF males’ hyperphagia and obesity. Intake was reduced similarly after RW and EE (around 15%), while BW reduction was around 8% and 1.5%, respectively. RW OLETF males reduced 32% retroperitoneal and inguinal fat and 39% visceral fat, while after EE the reduction was 21% and 13% respectively. Accordingly, leptin levels were reduced 33% after RW vs. 18% after EE. In contrast, OLETF females adhered to their genotype, presenting strong resistance to adiposity loss after both manipulations, with no evident beneficial responses. Male LETO responded to exercise by reducing intake and adiposity levels while females increased intake, BW and muscle mass. Enriched environment had no effect on LETO physiology. Overall, the moderation in adiposity observed after EE and RW in the OLETF males suggests that standard, impoverished conditions may exacerbate the hyperphagia and obesity of the males, worsening their phenotype. doi:10.1016/j.appet.2010.04.210
Psychosocial influence on diet preference and caloric intake in female monkeys M.E. WILSON ∗ , V. MICHOPOULOS Emory University, Atlanta, GA, USA Social dominance status in macaque monkeys functions to control aggression and access to resources. Because subordination is imposed through non-contact aggression, the continual harassment of subordinate females by more dominant animals emerges as a potent psychosocial stressor, resulting in periodic hypercortisolemia, less frequent targets of affiliative behavior, and increased anxiety behaviors, associated with changes in monoamine activity in limbic-hypothalamic regions. Social status differences are also evident in appetite and energy regulation. When fed a low fat high fiber diet, subordinates eat less, reflected in fewer and smaller meals, have lower body weight, less total body fat, and a hypometabolic condition. However, estimates of energy expenditure, assessed from activity patterns, do not show a social status difference. In contrast, when given a choice between this low caloric diet (LCD) and diet high in fat and sugar, subordinates consume significantly more calories, largely from the high caloric diet (HCD). While dominant females also prefer the HCD, they nonetheless show caloric restriction, consuming similar calories regardless of diet availability. Although stress hormone responsivity is not affected, the increased consumption of the HCD is anxiolytic in subordinate females whereas the removal of the HCD is anxiogenic in all females. The model provides the opportunity to examine the neurobiological mechanisms for understanding the comorbidity of anxiety and emotional feeding in females. Supported by NIH HD46501, F32-MH073525, RR00165 and NFS IBN 9876754. doi:10.1016/j.appet.2010.04.211
The leptin signaling cascade and pediatric obesity J.A. YANOVSKI National Institutes of Health, Bethesda, MD, USA The prevalence of overweight and obesity in children has tripled during the past 40 years. This alarming rise in body weight has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, this environment has not led to severe obesity in all children; rather, it has unmasked a select group of individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorie/low activity environment. This presentation will review inactivating mutations in the leptin signaling cascade that are associated with pediatriconset obesity and present some of the translational studies that have attempted treatment directed at correcting the observed defects. doi:10.1016/j.appet.2010.04.212
Anti-angiotensin type 1 receptor siRNA delivered into rat hypothalamus. A traceable reagent that reduces angiotensin binding, signal transduction and thirst D.K. YEE ∗ , L.A. FELGENDREDER, L.M. FLANAGAN-CATO University of Pennsylvania, Philadelphia, PA, USA Angiotensin II (AngII) is involved in the control of water and salt intake. Traditional approaches to study the cellular mechanisms that underlie these behaviors have relied on receptor ligands and other inhibitors injected into rat hypothalamus. These reagents have limitations: the extent of their diffusion in the brain is unknown and specific inhibitors are not available for many potential targets. Thus, we injected siRNA into rat brain targeting the AngII type 1 receptor (AT1R) as a platform to optimize procedures for other effective siRNA-mediated selective protein knockdown. First, we used an in vitro model (WB cells) to evaluate various AT1R siRNA sequence candidates. One siRNA candidate diminished AT1R levels by 90% and blocked any AngII-induced cell signaling compared to cells pretreated with luciferase (nonsilencing) siRNA. With the efficacy of an AT1R siRNA validated in WB cells, we began using this siRNA in vivo. Preliminary results have shown that rats treated with a single icv injection of AT1R siRNA substantially reduced their drinking responses to subsequent AngII injections compared to non-silencing siRNA at 22 h and 46 h. Furthermore, preliminary radioligand binding assays of the hypothalami of siRNA-treated rats demonstrated that AT1R siRNA diminished AT1R binding activity compared to the non-silencing siRNA. Experiments using biotin-tagged siRNAs are now planned to determine the extent of the affected areas by these reagents. Supported by NHLBI HL091314. doi:10.1016/j.appet.2010.04.213