Overconsumption of highly palatable calorically dense food is a major contributor to obesity and related metabolic disorders. This proposal investigates one of the neuropeptide systems thought to underlie neural integration of the rewarding value of food with input from gut-derived satiety signals, Glucagon-like peptide 1 (GLP-1). Preproglucagon (PPG, the precursor to GLP-1) neurons project to many brain areas where activation of GLP-1 receptors (GLP-1R) promotes satiety and reduces motivation for food. Most research has focused on one or another individual PPG neuron projection and GLP-1R population at a time, and although this has informed us about brain GLP-1 action, this approach does not provide broad insight into the functional organization of the central GLP-1 network. Here we will take advantage of transgenic mouse models to investigate GLP-1R neuron projections that mediate behavioral effects. We hypothesize that: 1) activation of some, and inhibition of other GLP-1R neuron projections reduce feeding; 2) that GLP-1R neurons in different brain nuclei receive synaptic input from unique brain regions; and 3) that GLP-1R neurons communicate with one another across brain regions. Based on our data implicating GLP-1R neurons of the Lateral Septum (LS) and Bed Nucleus of the Stria Terminalis (BNST) in feeding control, we focus on two exemplar cell populations: the LS GLP-1R neuron projection to Lateral Hypothalamus (LH); and the BNST GLP-1R neuron projection to the LH.
Aim 1 focuses on the GLP-1R LS-to-LH pathway, which we hypothesize promotes satiety and suppresses food reward when activated.
Aim 2 examines the GLP-1R BNST-to-LH projection, which we hypothesize works in the opposite direction, such that inhibition of these neurons promotes satiety and suppresses food reward. Experiments will test these hypotheses using a combination of cell type-specific chemogenetic and pharmacologic approaches to manipulate the activity of each of these GLP-1R neuron projections to LH. We will conduct detailed behavioral analyses to distinguish effects on satiation, satiety, motivation, and stress or malaise that can alter feeding, and we will use slice electrophysiology to characterize the underlying neuronal signaling pathways.
Aim 3 will determine sources of synaptic input to GLP-1R neurons in each location, testing the hypothesis that they receive distinct sources of input from PPG and other neurons, including GLP-1R+ neurons in other nuclei. Studies in this aim will apply a combination of traditional retrograde tracing and cutting edge cell type- and anatomic pathway-specific mono- and transsynaptic viral tracing methods. Together, our results will elucidate new mechanisms for GLP-1's hypophagic effects, identify new cell type-specific neuronal pathways that play a role in brain control of feeding, and provide a more complete picture of how PPG neurons and GLP-1-receptive cells throughout the brain coordinate to influence behavior. We propose that central GLP-1 signaling pathways are not unique in their integrated network organization, and expect that our findings will serve as a template for assessing these same questions for other circuits.
This project examines brain Glucagon-like Peptide 1, one of the neural systems that controls food intake by integrating factors including food palatability, motivation, and gastrointestinal signals that relate to the presence or absence of nutrients in the gut. Dysfunction in neural systems such as this is thought to underlie chronic overeating, obesity, and other related metabolic disorders, and so improved understanding of this circuitry will help to identify biological factors that contribute to the development and maintenance of these problems. The results of these studies also have the potential to identify new targets for pharmacologic treatment of obesity and overeating, which are sorely needed.
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|Terrill, Sarah J; Jackson, Christine M; Greene, Hayden E et al. (2016) Role of lateral septum glucagon-like peptide 1 receptors in food intake. Am J Physiol Regul Integr Comp Physiol 311:R124-32|
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|Williams, Diana L (2014) Neural integration of satiation and food reward: role of GLP-1 and orexin pathways. Physiol Behav 136:194-9|
|Dossat, Amanda M; Diaz, Ryan; Gallo, Lindsay et al. (2013) Nucleus accumbens GLP-1 receptors influence meal size and palatability. Am J Physiol Endocrinol Metab 304:E1314-20|