The contribution of non-homeostatic factors to the recent increase of obesity incidence in Westernized populations such as the U.S., has now come to be appreciated. Ready availability and affordability of palatable, high caloric density foods;activation of responsive CNS pathways that mediate motivation and reward;and loss of effectiveness of endocrine adiposity signals to act at the CNS, may all contribute to excess caloric intake. Our lab has focused on the potential role of the candidate adiposity signals insulin and leptin to modulate 'food reward behavior'. Insulin and leptin act at the medial hypothalamus to regulate energy homeostasis;they also act at CNS sites that mediate reward and motivation. Both decrease performance in behavioral tasks which assess food reward. This occurs at doses that are subthreshold for effects on long-term energy homeostasis, which suggests that the reward-suppressive effects of insulin and leptin are independent of their chronic effects to decrease food intake and regulate body weight. Our recent studies demonstrate that both the medial hypothalamic arcuate nucleus (ARC) and the ventral tegmental area (VTA) are direct sites of action for insulin and leptin to inhibit food reward;and that the effectiveness of insulin and leptin is reversed by high fat diet background. These new insights lead to new questions which will be addressed by pursuing the Specific Aims summarized below.
These Aims will evaluate anatomical, behavioral, and developmental aspects of food reward modulation by insulin and leptin. The long-term objective is to delineate the behavioral and synaptic mechanisms that modulate food reward, in relationship to diet or nutritional status. The current Aims will build towards that objective by evaluating: 1) the ability of insulin, leptin, or cell signaling inhibitors to modulate performance in a behavioral task that models diet recidivism, relapse to sucrose-seeking;2) the effect of high fat diet experience on sucrose self-administration in pre- and post-pubertal rats;and 3) the CNS sites activated in response to sucrose self-administration and modulation of this activation by insulin, leptin, or cell-signaling inhibitors. These studies will elucidate key brain regions and cell signaling pathways which modulate food reward and are targets for insulin and leptin. This could provide the basis for potential therapeutic intervention strategies targeting non-homeostatic, 'reward-based'feeding, a public health problem that is relevant for both adult and pediatric populations in the U.S.

Public Health Relevance

The contribution of excessive calorie intake, based on the availability of inexpensive, highly palatable food that also happens to be high in sugar and fat, to the current increase in obesity severity and prevalence among both adult and pediatric populations is an enormous public health problem. We have identified two hormones which can curb animal models of this reward-based feeding, and propose to study where in the brain and how in the brain they are having their effects (since use of these hormones themselves as the basis for therapeutic or behavioral interventions is not a viable possibility). Importantly we are following up on new pilot data that suggest that young rats are more motivated for sweet solutions than adult rats in our lab, and we observe an effect of high fat diet. Our experiments thus model one aspect of the eating habits of people in 'Westernized'societies such as the U.S. and may provide translational insight into dealing with this excessive intake.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Yanovski, Susan Z
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Seattle Institute for Biomedical/Clinical Research
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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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