Obesity has reached epidemic proportions in the United States, and both genetic and environmental contributions to the development and maintenance of obesity have been identified in human studies and animal models. Recent rodent models of genetic obesity have hypothalamic signaling pathways related to the overall control of metabolism and energy balance. Unlike these strains, the obese Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a unique genetic model of obesity with an identified deficit in a peripheral gut-brain peptide signaling pathway critical to the within meal control of food intake. OLETF rats spontaneously lack the promoter region for the gene that encodes for the cholecystokinin (CCK) A receptor, the subtype that mediates the satiety actions of this meal-elicited peptide. OLETF rats are obese and hyperphagic, and we have shown that their hyperphagia is characterized by increased meal size, consistent with the lack of a meal related signal important in the negative feedback control of food intake. In this proposal, we hypothesize that OLETF hyperphagia and obesity: 1) depends upon their genetically determined inability to detect meal-related CCK negative feedback signals critical in the control of meal size, and 2) is not dependent on altered central nervous system processing of other metabolic and hypothalamic signals important in the overall control of energy balance. Experiments in this proposal are designed to address multiple aspects of this hypothesis. Specifically, we will: 1) identify the roles of increased meal size and hyperphagia in the development of obesity in OLETF rats, 2) characterize metabolic profiles and patterns of hypothalamic gene expression in ad lib and pair fed OLETF rats, 3) identify potential interactions between exercise and disordered patterns of food intake in OLETF rats, 4) characterize OLETF feeding and metabolic responses to high fat and macronutrient selection diets and 5) compare the OLETF rat to a newly available CCK-A knockout mouse that does not develop obesity. Together, results from these studies will: 1) identify and characterize the ways in which a unique genetic deficit in a peripheral satiety signaling pathway interacts with a range of environmental factors (exercise, dietary restriction, diet composition) to modulate the development and maintenance of obesity, and 2) identify how such a satiety deficit interacts with central hypothalamic pathways mediating the control of energy balance.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1-SSS-T (02))
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Yanovski, Susan Z
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Johns Hopkins University
Schools of Medicine
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Kim, Yonwook J; Schroeder, Mariana; Liang, Nu-Chu et al. (2017) Effects of early postnatal environment on hypothalamic gene expression in OLETF rats. PLoS One 12:e0178428
Bi, Sheng; Moran, Timothy H (2016) Obesity in the Otsuka Long Evans Tokushima Fatty Rat: Mechanisms and Discoveries. Front Nutr 3:21
Schroeder, Mariana; Kronfeld-Schor, Noga; Weller, Aron (2013) Selective leptin insensitivity and alterations in female-reproductive patterns linked to hyperleptinemia during infancy. PLoS One 8:e59937
Zhu, Guangjing; Yan, Jianqun; Smith, Wanli W et al. (2012) Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis. Physiol Behav 105:234-41
Bi, Sheng; Kim, Yonwook J; Zheng, Fenping (2012) Dorsomedial hypothalamic NPY and energy balance control. Neuropeptides 46:309-14
Marco, Asaf; Schroeder, Mariana; Weller, Aron (2012) Feeding and reward: ontogenetic changes in an animal model of obesity. Neuropharmacology 62:2447-54
Schroeder, Mariana; Gelber, Vered; Moran, Timothy H et al. (2010) Long-term obesity levels in female OLETF rats following time-specific post-weaning food restriction. Horm Behav 58:844-53
Schroeder, Mariana; Moran, Timothy H; Weller, Aron (2010) Attenuation of obesity by early-life food restriction in genetically hyperphagic male OLETF rats: peripheral mechanisms. Horm Behav 57:455-62
Schroeder, Mariana; Shbiro, Liat; Moran, Timothy H et al. (2010) Maternal environmental contribution to adult sensitivity and resistance to obesity in Long Evans rats. PLoS One 5:e13825
Schroeder, Mariana; Schechter, Michal; Fride, Ester et al. (2009) Examining maternal influence on OLETF rats' early overweight: insights from a cross-fostering study. Dev Psychobiol 51:358-66

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