Satiety hormones such as glucagon-like peptide-1 (Glp1) are secreted in response to feeding and activate neural processes that subsequently suppress food intake. While the satiety effects of Glp1 have been known for over 15 years, the mechanism mediating this effect is not clearly defined. This is significant since some Glp1-based therapies for type 2 diabetes display modest weight loss effects. Understanding how Glp1 regulates food intake may, therefore, lead to the design of therapeutic interventions with improved efficacy for weight loss. Based on our preliminary data, we hypothesize that the anorectic effect mediated via the central Glp1 receptor (Glp1r) is integrated with hypothalamic signaling proteins that respond to changes in circulating glucose. Activation of the hypothalamic Glp1 receptor (Glp1r) inhibits the cellular energy sensor AMP-activated protein kinase (AMPK). Considering that the anorectic effects of leptin, insulin and glucose are mediated in part by inhibition of hypothalamic AMPK, we hypothesize that this is also a mechanism by which Glp1 suppresses food intake. We also show that inhibition of AMPK by the Glp1r agonist Exendin-4 (Ex4) in hypothalamic cell lines occurs only with increasing glucose concentration. Ex4 also stimulates glucose uptake and metabolism in a glucose concentration-dependent manner. Since increased glucose metabolism inhibits AMPK, we hypothesize that central Glp1r activation inhibits AMPK and subsequently reduces food intake by stimulating central glucose metabolism. Supporting this hypothesis, we show that inhibition of glycolysis in the brain blocks the anorectic effect of Ex4. Contrasting the effects of glucose, central administration of fructose attenuates the anorectic effect of Ex4. Fructose activates hypothalamic AMPK. This suggests that by activating hypothalamic AMPK fructose can "short-circuit" the Glp1r signaling pathway and promote central Glp1 resistance. This could partially explain our observation that mice fed a sucrose diet, which provides fructose and glucose, eat more compared to mice fed an isocaloric starch diet that only provides glucose. This also has clinical implications based on the association between increased fructose consumption and the obesity epidemic, particularly in children. Since the Glp1r is expressed in multiple hypothalamic nuclei, the first aim is to identiy hypothalamic regions mediating the anorectic effect of Glp1r agonists.
The second aim will combine hypothalamic nuclei- specific modulation of the Glp1r with pharmacological agents that target processes we hypothesize are downstream of the Glp1r - glucose metabolism and AMPK activity.
The final aim will assess whether dietary fructose is an inhibitor of the satiety effects mediated by central Glp1r activation. The long-term goal of this application is to elucidate the mechanisms that regulate multiple aspects of feeding behavior. Defining the mechanisms by which the central Glp1r regulates food intake will identify key control points that could be sites for disruption by obesogenic factors and targets for therapeutic intervention.

Public Health Relevance

Obesity is a significant risk factor for cardiovascular disease, type 2 diabetes and even cancer. A significant contributor to the obesity epidemic is the failure of hormones that control food intake. The aim of this proposal is to identify the mechanisms by which one of these hormones, glucagon-like peptide-1, prevents excess food intake and how certain diets rich in sugar can interfere with these mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097361-01A1
Application #
8577512
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Hyde, James F
Project Start
2013-07-12
Project End
2018-04-30
Budget Start
2013-07-12
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$424,125
Indirect Cost
$206,625
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037