The Glucagon‐Like Peptide‐1 (GLP‐1) System is Modulated by Acute and Chronic Exposure to Alcohol: Findings from Human Laboratory and Brain Postmortem Studies
Authors: Farokhnia Mehdi , Lee Mary R , Sun Hui , Suchankova Petra , Leggio Lorenzo 
Published: June 2021

Glucagon‐Like Peptide‐1 (GLP‐1) is a 30‐amino acid peptide primarily produced by endocrine cells in the intestines. As an incretin, GLP‐1 regulates food intake and glucose homeostasis via central (e.g., hypothalamus) and peripheral (e.g., pancreas) mechanisms. GLP‐1 also acts as a neuropeptide and both the peptide and it receptor (GLP‐1R) are expressed in the brain. Previous data suggest that GLP‐1 signaling is involved in regulating neurobiological pathways related to addictive behaviors, including alcohol use disorder (AUD). Therefore, GLP‐1R has begun to be investigated as a potential therapeutic target for AUD. To this end, it is also important to understand how alcohol use may affect the endogenous GLP‐1 system. In a series of human laboratory experiments, we first examined the effect of alcohol administration on peripheral GLP‐1 concentrations in heavy‐drinking alcohol‐dependent individuals. Four separate sessions were conducted across these studies: oral self‐administered (variable dose) alcohol, oral fixed dose alcohol, intravenous self‐administered (variable dose) alcohol, and intravenous fixed‐dose alcohol. Repeated blood samples were obtained during each session and GLP‐1 concentrations were measured via ELISA. In all four experiments, acute administration of alcohol consistently resulted in a significant reduction in peripheral GLP‐1 concentrations (p's < 0.001). Next, we looked at the GLP‐1R gene expression in postmortem brain tissues from patients with AUD and healthy controls (New South Wales Tissue Resource Centre, University of Sydney). GLP‐1R mRNA was extracted from five brain regions (i.e., prefrontal cortex, ventral tegmental area, nucleus accumbens, amygdala, and hippocampus), and real‐time quantitative PCR with TaqMan gene expression assay was run. Results showed that fold change in GLP‐1R mRNA in the hippocampus was significantly higher in patients with AUD compared to healthy controls (p = 0.007). Collectively, these data elucidate, for the first time to our knowledge, how exposure to alcohol influences different components of the GLP‐1 system, both in the periphery and the in the brain. Future studies should investigate the safety and efficacy of targeting the GLP‐1 system (for example with GLP‐1 analogs already approved for diabetes and obesity) as a novel pharmacological approach to treat AUD.Support or Funding InformationThis work was supported by A) NIH intramural funding ZIA‐AA000218 (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology), jointly supported by NIAAA Division of Intramural Clinical and Biological Research and NIDA Intramural Research Program, and B) NIH Center on Compulsive Behaviors, funded by the NIH Deputy Director for Intramural Research (DDIR) Innovation Award. Brain tissues were received from the New South Wales Brain Tissue Resource Centre (NSWBTRC) at the University of Sydney, which is supported by NIAAA under Award Number R28AA012725 and Neuroscience Research Australia.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.