It is well-established that actions of insulin in the brain affect feeding. However, very little is known about the underlying mechanisms (see Fernandez and Torres-Aleman, 2012 for review). A handful of studies suggest that insulin modulates the function of brain reward and motivation systems that are involved in food-seeking and feeding behavior such as the nucleus accumbens (NAc). For example, activation of insulin receptors enhances dopamine release in the NAc and decreases food intake when infused into the NAc (Stouffer et al, 2015; Figlewicz et al, 2006). In addition, one study has shown that insulin reduces excitatory transmission in the VTA and a few studies in younger animals have found that insulin modulates AMPA receptor (AMPAR) synaptic trafficking in cortical neurons (Beattie et al, 1995; Labouebe et al, 2013; Liu et al, 2013). Excitatory transmission via AMPARs in the NAc increases motivation for food (Di Ciano et al, 2001). However, the effect of insulin on NAc excitatory transmission or food-seeking is unknown. Our long-term goal is to understand how NAc excitatory transmission and food-seeking behavior are modulated by insulin. Our preliminary data suggest that insulin receptor activation increases excitatory transmission in the NAc via mechanisms involving nitric oxide and enhanced glutamate release, and that diet-induced obesity reduces the effects of insulin on NAc excitatory transmission. Furthermore, we found that intra-NAc insulin enhanced food- seeking behaviors in non-obese rats. The main objectives of the proposed studies are to determine the mechanism by which insulin receptor activation enhances NAc excitatory transmission, and the effect of insulin receptor activation on food-seeking behavior in non-obese and obese rats. These studies will provide a fundamental information about the effects of insulin on NAc function and the role of insulin in food-seeking in the non-obese and obese state.

Public Health Relevance

Over 30% of the U.S. population is struggling with obesity, which contributes to the development of type 2 diabetes, cardiovascular disease, and many cancers. The goal of the proposed work is to provide evidence- based, targeted approaches for the treatment and prevention of obesity. Increased food craving in obese people hampers weight loss. Our goal is to understand how insulin effects the function of brain circuits that control food craving in the normal and obese state. This work will provide a mechanistic foundation for the development of novel approaches for treating and preventing obesity and will provide critical fundamental insights into the role of insulin in motivation and reward.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Yanovski, Susan Z
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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