The current 'epidemic' of obesity in the United States has been ascribed to environmental changes that have occurred over the past two decades. Prominent in this is the ready economic availability of highly palatable, high caloric density foods. Although numerous studies have focused on hormones such as insulin and leptin, and neurotransmitters, which act at the medial hypothalamus to regulate calorie intake, little attention has focused on the potential regulation of central nervous system (CNS) circuitry which mediates the rewarding or motivating aspects of food. This circuitry includes the midbrain dopamine neurons (DA) as well as other forebrain areas with which the medial hypothalamus has extensive direct and indirect connections. Our lab has evidence that the candidate adiposity signals insulin and leptin decrease performance in behavioral tasks that assess food reward and that require DA signaling. We hypothesize that the midbrain DA neurons whose cell bodies are in the ventral tegmental area (VTA) serve as a direct target for insulin and leptin. In this proposal we will test this hypothesis in rats by studying the effects of insulin or leptin infused directly into the VTA on behavioral procedures that evaluate different aspects of food reward/motivation: a free-feeding ingestive task, the conditioned place preference, and self-administration. We will compare sweet vs. fat food reward in these tasks, to evaluate macronutrient specificity. We will infuse insulin receptor antisense oligonucleotides directly into the VTA to determine the role of endogenous insulin signaling in modulation of food reward behavior. Because VTA DA neurons express insulin and leptin receptors, we will measure insulin- and leptin-stimulation of the PI3 kinase pathway as an index of direct VTA activation at the cellular level. Comparable studies will be carried out in rats fed a defined high fat diet snack in addition to chow, a model of CNS insulin resistance that we have recently developed. We will use this model to test whether the behavioral and cellular actions of insulin and/or leptin at the VTA are blunted by high fat diet ingestion, i.e., a model of VTA insulin or leptin resistance. Together these studies will evaluate the potential regulation of reward circuitry and function in the CNS by adiposity signals. Findings from these studies will contribute to the long-term goal of learning whether altered food reward value contributes to the (relative) overeating which occurs in association with the availability of highly palatable foods, independent of caloric need.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Yanovski, Susan Z
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University of Washington
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Figlewicz, Dianne P; Jay, Jennifer; West, Constance H et al. (2018) Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat. Am J Physiol Regul Integr Comp Physiol 314:R191-R200
Figlewicz, Dianne P (2016) Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat: Historical perspective. Brain Res 1645:68-70
Figlewicz, Dianne P (2015) Modulation of Food Reward by Endocrine and Environmental Factors: Update and Perspective. Psychosom Med 77:664-70
Figlewicz, D P; Hill, S R; Jay, J L et al. (2014) Effect of recurrent yohimbine on immediate and post-hoc behaviors, stress hormones, and energy homeostatic parameters. Physiol Behav 129:186-93
Stice, Eric; Figlewicz, Dianne P; Gosnell, Blake A et al. (2013) The contribution of brain reward circuits to the obesity epidemic. Neurosci Biobehav Rev 37:2047-58
Figlewicz, Dianne P; Jay, Jennifer L; Acheson, Molly A et al. (2013) Moderate high fat diet increases sucrose self-administration in young rats. Appetite 61:19-29
Seaquist, Elizabeth R; Lattemann, Dianne Figlewicz; Dixon, Roger A (2012) American Diabetes Association research symposium: diabetes and the brain. Diabetes 61:3056-62
Overduin, Joost; Figlewicz, Dianne P; Bennett-Jay, Jennifer et al. (2012) Ghrelin increases the motivation to eat, but does not alter food palatability. Am J Physiol Regul Integr Comp Physiol 303:R259-69
Davis, Jon F; Choi, Derrick L; Schurdak, Jennifer D et al. (2011) Leptin regulates energy balance and motivation through action at distinct neural circuits. Biol Psychiatry 69:668-74
Figlewicz, Dianne P; Bennett-Jay, Jennifer L; Kittleson, Sepideh et al. (2011) Sucrose self-administration and CNS activation in the rat. Am J Physiol Regul Integr Comp Physiol 300:R876-84

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