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.
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.
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.