The overarching goal of the Hayes lab is to identify and characterize the neural signaling pathways controlling for food intake and body weight regulation in an effort to treat obesity and associated co-morbidities. To this end, our research examines the behavioral, intracellular, neuronal and endocrine mechanisms governing energy balance and how these processes are dysregulated in obesity.
A major theme of research in our lab focuses on the neuropeptide glucagon-like peptide-1 (GLP-1) and its role in regulating energy balance through action in the periphery on the vagus nerve (cranial nerve X), as well as the central nervous system (CNS). The potential for GLP-1 receptor agonists to be used as a pharmacological treatment for obesity has been highlighted in a number of recent publications. For this to become a reality, however, will require a deepened understanding of the behavioral, neuronal, and physiological mechanisms by which the peripheral and central GLP-1 systems control for food intake and body weight regulation.
Reward / Motivated Feeding: Why We Override Our Satiation Signals.
It is clear that the excessive food intake, especially of palatable foods, that contributes to human obesity is not driven by metabolic need alone. While our lab investigates the importance of neuropeptide signaling on vagal afferents and in hindbrain and hypothalamic nuclei for the homeostatic control of food intake, it is also critical to examine and better define the neural basis of non-homeostatic controls of food intake.
Ongoing extensive investigations in our lab are examining the neuroendocrine systems that connect within-meal inhibitory feedback from gastrointestinal satiation signals to nuclei in the mesolimbic reward system (MRS), including the ventral tegmental area and nucleus accumbens. Activation of the MRS by these neuroendocrine systems is postulated to decrease motivation to continue feeding, leading to meal termination. Thus, current projects are investigating the behavioral, molecular, neuronal and physiological mechanisms by which energy balance-relevant neuropeptides (such as glucagon-like peptide-1, leptin and amylin) are modulating the non-homeostatic controls of feeding mediated by nuclei in the MRS.
Integrative Systems Neuroscience of Energy Balance
While the CNS control of energy balance involves redundant and anatomically distributed processing across the CNS, a few nuclei, such as the nucleus tractus solitarius (NTS) of the hindbrain, stand out as essential for the processing and integration of a variety of ascending and descending pathways controlling for food intake and energy balance. It is also very clear that more progress could be made in the treatment of obesity if research focused attention on these specific CNS nuclei that serve as hubs for the neural control of energy balance. Thus, our lab explores the intracellular mechanisms by which multiple neurochemical systems interact and synergize at the level of the NTS to control for energy balance.
From Hunger to Nausea: Points on the same spectrum of ingestive behavior.
More than 1.6 million cases of cancer are diagnosed yearly in the United States. The toll on the patient can be life-threatening, and unfortunately the pharmacological- and radiation-treatment options for cancer are commonly accompanied by a host of undesirable side effects (pain, diarrhea, anorexia, nausea, vomiting). The severity of these side effects can cause cancer patients to delay or refuse chemotherapy, in turn leading to increased patient morbidity and mortality. With approximately 80% of chemotherapy patients experiencing chemotherapy-induced nausea and vomiting, there is an urgent need to develop more effective anti-emetic and anti-nausea treatments to improve the quality of life for cancer patients undergoing chemotherapy and/or radiation therapy.
Similar to the widely accepted view of nausea being a major side effect for cancer treatment, nausea and/or vomiting are the primary adverse events (i.e. side effects) reported in many patients receiving pharmacotherapy for Type 2 Diabetes Mellitus (T2DM). Indeed, ~20-50% of T2DM patients maintained on the GLP-1R agonists (liraglutide and exendin-4) report nausea/vomiting, and yet there is very little investigation of the mechanisms mediating the nausea/malaise and virtually no understanding of the significance of nausea/malaise in relation to GLP-1 receptor-mediated suppression of food intake.
Although rodents lack the physiology needed to vomit, behavioral paradigms such as pica (ingestion of non-nutritive substances) and conditioned taste avoidance (CTA) are used commonly in both rats and mice as models for the study of malaise and nausea. Our lab utilizes these well-established rat models of malaise to determine the neural pathways and physiological mechanisms responsible for mediating the nausea/malaise induced by GLP-1 receptor ligands and chemotherapy drugs, as well as to determine whether the nausea/malaise is correlated or causal for the intake-inhibitory effects of GLP-1 receptor-targeting pharmaceuticals.
De Jonghe BC, Holland R, Olivos DR, Rupprecht LE, Kanoski SE, Hayes MR: Hindbrain GLP-1 receptor mediation of cisplatin-induced anorexia and nausea. Physiology and Behavior 153: 109-114, 2016.
Kanoski SE, Hayes MR, Skibicka KP: GLP-1 and weight loss: Unraveling the diverse neural circuitry. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology 310(10): R885-895, 2016.
Hayes MR, Schmidt HD: GLP-1 influences food and drug reward. Current Opinion in Behavioral Sciences 9: 66-70, 2016.
Ashare RL, Kimmey BA, Rupprecht LA, Bowers MA, Hayes MR, Schmidt HD: Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers. Translational Psychiatry 6: e713, 2016.
Schmidt HD, Mietlicki-Baase EG, Ige KY, Maurer JJ, Reiner DJ, Zimmer DJ, Van Nest DS, Guercio LA, Wimmer ME, Olivos DR, De Jonghe BC, Hayes MR: Glucagon-like peptide-1 receptor activation in the ventral tegmental area decreases the reinforcing efficacy of cocaine. Neuropsychopharmacology 41(7): 1917-1928, 2016.
Reiner DJ, Mietlicki-Baase EG, McGrath LE, Zimmer DJ, Bence KK, Sousa GL, Konanur VR, Krawczyk J, Burk DH, Kanoski SE, Hermann GE, Rogers RC, Hayes MR: Astrocytes regulate GLP-1 receptor-mediated effects on energy balance. Journal of Neuroscience 36(12): 3531-3540, 2016.
Reiner DJ, Mietlicki-Baase EG, McGrath LE, Turner CA, Koch-Laskowski KL, Bence KK, Hermann GE, Rogers RC, Hayes MR: GLP-1 receptors expressed on NTS astrocytes regulate energy balance. The Obesity Society Annual Meeting, Los Angeles, CA November 2015 Notes: Poster Presentation.
Mietlicki-Baase EG, McGrath LE, Pham TN, Chan TN, Krawczyk, Hayes MR: VTA amylin receptor activation modulates macronutrient selection. The Obesity Society Annual Meeting, Los Angeles, CA November 2015 Notes: Poster Presentation.
Hernandez NS, Mietlicki-Baase EG, Maurer JJ, Van Nest DS, Hayes MR, Schmidt HD: Glucagonlike peptide-1 receptor activation in the ventral tegmental area or the nucleus accumbens attenuates cocaine seeking in rats. Society for Neuroscience Annual Meeting, Chicago, IL October 2015 Notes: Poster Presentation.
Reiner DJ, Kanoski SE, Hayes MR: GLP-1 receptor signaling in the lateral dorsal tegmental area is physiologically required for the regulation of food intake and body weight. Society for the Study of Ingestive Behavior Annual Meeting, Denver, CO July 2015 Notes: Poster Presentation.
back to top
Last updated: 04/06/2018
The Trustees of the University of Pennsylvania