Neuroendocrine Control of Energy Balance
Our laboratory’s overarching goal seeks to understand the neuroendocrine systems regulating energy balance and motivated behaviors. Using multiple approaches from the cell to the whole organism and extensively examine the role of various neuroendocrine signaling systems (e.g., GLP-1, leptin, amylin, CCK, serotonin, glutamate, and dopamine) in peripheral and central control of food intake and body weight regulation.
Overall, our research program takes a novel systems-neuroscience approach aimed at enhancing the development of realistic pharmacological-based therapeutics to treat obesity and associated comorbidities (e.g. obesity, eating disorders, diabetes, drug addiction and nausea / malaise).
The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1
These data contribute to a growing body of evidence that highlights the LC as a feeding-relevant nucleus. As the LC is known to express receptors for other neuropeptides relevant to energy balance regulation, future investigations aimed at characterizing the endogenous mechanism by which the LC participates in food intake control are warranted. Here, we characterize a previously unexplored site of action for endogenous and exogenous GLP-1 signaling. We show that LC GLP-1R activation suppresses food intake, engages autonomic responses, and results in illness-like behaviors. This insight is necessary to advance clinical strategies for the treatment of obesity with improved GLP-1 analogs, with the hope of mitigating the nausea pervasive to current existing GLP-1–based pharmacotherapies.
Amylin Modulates a Ventral Tegmental Area-to-Medial Prefrontal Cortex Circuit to Suppress Food Intake and Impulsive Food-Directed Behavior
The VTA and mPFC are implicated in behaviors related to reward seeking, impulsivity, and attention around feeding and other hedonic stimuli. This is the first study to investigate how a satiation hormone affects mesocortical pathway activity and food reward–directed behaviors. Using multiple behavioral, pharmacological, and genetic approaches, we demonstrated that amylin signaling in the VTA reduced palatable food intake, impulsive behavior for a food reward, and mPFC dopamine release, likely through activation of local VTA GABA neurotransmission and inhibition of VTA-to-mPFC projecting dopamine neurons.
GIP receptor agonism blocks chemotherapy-induced nausea and vomiting
In collaboration with Eli Lilly, this work demonstrates in three different mammalian species that GIPR signaling is capable of antagonizing emesis and nausea induced by chemotherapy treatment by counteracting the shift toward an excitatory glutamatergic signaling in areas of the brain critical for the mediation of emesis and nausea. These results highlight a potential new clinical use for GIP analogs to increase the efficacy of current therapeutic regimes for the treatment of nausea and emesis in oncology patients.
GPR-160 Receptor Signaling in the Dorsal Vagal Complex of Male Rats Modulates Meal Microstructure and CART-Mediated Hypophagia
This work shows that DVC GPR-160 signaling is at least partially responsible for CART’s well-established anorexigenic effects when delivered to the brainstem at pharmacological doses. This work also shows that DVC GPR-160 endogenous signaling regulates normal meal microstructure and begins to characterize the DVC cell types that express Gpr160.
Metabolic hormone action in the VTA: Reward-directed behavior and mechanistic insights
This review provides a comprehensive update of the regulation of midbrain dopamine circuits by peripheral feeding hormones, cataloging what is currently known about the mechanisms by which these hormones influence VTA activity and how these actions regulate food intake and behavior around drugs of abuse. Better understanding of the reward-modulating effects of these hormone systems will help develop more effective treatments for obesity and addictive disorders.
Tirzepatide suppresses palatable food intake by selectively reducing preference for fat in rodents
In collaboration with Eli Lilly, we showed that the dual GLP-1/GIP agonist Tirzepatide robustly decreases preference for palatable foods by selectively decreasing lipid consumption. Our preclinical findings highlight that promoting healthier food options may contribute to the weight-loss success of therapeutic Tirzepatide use for patients.
Corrination of a GLP-1 Receptor Agonist for Glycemic Control without Emesis
In collaboration with Syracuse University professor Dr. Robert Doyle, our labs created a conjugated GLP-1R agonist (Cbi-Ex4) with reduced brain penetrance that enhances glycemic control without inducing emesis or anorexia. Our preclinical findings highlight its potential therapeutic use for patients seeking improved glycemic control without the loss of appetite and emesis characteristic of current GLP-1 therapeutics.
GIP Receptor Agonism Attenuates GLP-1 Receptor Agonist Induced Nausea and Emesis in Preclinical Models
Our research uncovered that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance.
GDF15 Induces Anorexia through Nausea and Emesis
Assessing whether or not GDF15 produces emesis and/or emetic- like behaviors in the vomiting shrew (Suncus murinus) and non-vomiting rat.
GLP-1 Receptors action on brainstem GABA neurons
Examining the contribution of nucleus tractus solitarius (NTS) glucagon-like peptide-1 receptors (GLP-1Rs) to the anorectic potential of the FDA-approved obesity drug liraglutide and highlights a phenotypically distinct (GABAergic) population of neurons within the NTS that express the GLP-1R and are involved in the mediation of liraglutide signaling