The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Edgar T Walters
Benjamin R Arenkiel
Zheng (Jake) Chen
Qi Lin Cao
From 1960-2016, U.S. obesity prevalence increased 13-40% and diabetes increased from 3-15%. There is an epidemic of metabesity, the aggregate metabolic disorders produced by chronic overeating. Drugs for metabesity were developed in the 1930s with limited effectiveness; agents today rely on the same principles and are similarly ineffective. Particularly surprising has been the failure of satiety enhancers; this indicates it may not be that physiologic hunger drives chronic overeating. Although hunger and satiety affect traditional reward circuitry (Cassidy & Tong 2017), evidence for the primacy of this effect is mixed. Being hungry reduces anxiety-like behavior in mice; whether the act of eating also reduces anxiety is not well-known. If true, this represents a different avenue for the beneficial effects of eating than just reward manipulation or satiation. The aim of this dissertation is to discover hypothalamic neurocircuits involved in this relationship.
This body of work is the result of two projects in mice. In the first project, I demonstrate that GABAergic eating neurons in the lateral hypothalamus (LH) inhibit GABAergic anxiety neurons in the basal forebrain (BF). Activating this circuit causes feeding and reduces anxiety; fiber photometry shows LH neurons are active both during food approach and food consumption, but BF neurons only drop in activity during eating. Conversely, BF neurons activate in response to environmental anxiogenic stimuli. It appears that the act of eating can, through the LH-BF circuit, directly reduce sensitivity to threatening stimuli The second project is in collaboration with Yuanzhong Xu and Yungang Lu on a parallel circuit from the paraventricular hypothalamus (PVH) glutamatergic projections to the ventral lateral septum (LSv) GABA neurons. My work with fiber photometry shows that both the PVH and LS respond to anxiety-provoking stimuli and are silenced by food, but with divergent activation/deactivation dynamics.
This data shows at the circuit level that the act of eating itself, not hunger per se, reduces activity of anxiety regions in the brain via hypothalamic neurocircuits. It may be that some metabesity arises from chronic overeating of food eaten for anxiolytic manipulation of these circuits, a concept popularly called "stress eating". Until this behavior is addressed by new psychotherapy or pharmacology, these patients will likely struggle to recover.
lateral hypothalamus, basal forebrain, obesity, metabesity, inhibition, optogenetics