The Dynamic Nature of the POMC Neuron Landscape, and the Impact of POMC Peptides and Body Composition States in Motivated Feeding
Jones, Graham
2019
Abstract
The importance of proopiomelanocortin (POMC) in maintaining normal metabolic homeostasis is well established. However, due to the phenotypes associated with human-patients and animal models with dysfunctional melanocortin systems, this propeptide and the neurons that produce it are dogmatically cast into an oversimplified role as merely being the satiety-signaling counterpart to the hunger-signaling agouti-related peptide (AgRP) neurons. In actuality POMC neurons represent an extremely diverse cell population, whose impact and function increase in complexity as our understanding grows. In my thesis I explore the anatomical and behavioral landscape of neuronal POMC in the mouse. First, I discuss the heterogeneity of POMC neurons and the paradoxical relationships associated with POMC-derived peptides and their neurotransmitter identities. POMC neurons are known to be both glutamatergic and/or GABAergic, which are predominantly excitatory and inhibitory, respectively. Yet methodological differences used to measure these characteristics the relative proportions reported for each subpopulation are unresolved. Deciphering the relationship between these fast neurotransmitters in POMC neurons is critical to being able to place POMC neurons into the proper short-term contexts of homeostatic regulation. The POMC propeptide is processed into α-melanocyte stimulating hormone (α-MSH) and β-endorphin (β-End), which respectively suppress and stimulate feeding. Pharmacology and genetic models have taught us a lot about these signaling hormones, but their specific roles are still unclear. Next, I investigated the histological overlap between POMC-peptide and a lineage trace for glutamate neurons, finding that there was an even split in glutamatergic and non- glutamatergic- POMC neurons. Then I assessed the impact of restoring Pomc expression specifically to glutamatergic neurons, using a Cre recombinase reversible Pomc-deficient mouse and a glutamate-neuron specific Cre driver. This resulted in a nearly complete normalization of the POMC system, including the presence of GABAergic POMC neurons, contradicting the lineage trace data. Together these findings uncovered a previously unknown phenomenon, wherein POMC neurons can exhibit plasticity in their neurotransmitter identity. This work finished with triple-label in situ hybridization (ISH) for Pomc, Vglut2 (a glutamate neuron-associated gene), and Gad67 (a GABA neuron-associated gene). Overlap between all of the labels revealed a sizeable population of Pomc neurons that express both Vglut2 and Gad67, and that there is a distinct rostral-caudal pattern in the localization of Pomc neurons that express one or both of the markers. Finally, I studied the behavioral impact of Pomc-deficiency, obesity, weight loss, Pomc-restoration after weight loss, and agonism of melanocortin receptors (MCRs) in operant feeding. I utilized two mouse models of obesity, Pomc-deficient mice and diet-induced obese (DIO) mice, and assessed their feeding behavior while obese, following weight loss to normal body mass, and after restoring Pomc in animals that had lost weight. Between these groups I found that weight loss and Pomc-deficiency each uniquely impart an increased drive to earn and eat food, and that they act additively in Pomc-deficient mice who have lost weight. I then showed that a history of weight loss intensifies future mild hunger, without a lasting impact on basal drive. Next, I established that the increase in operant feeding performance is correlated with the degree of weight loss. Then, I showed that hyperleptinemia potentiates the drive to earn food, but not eat it, after leptin sensitivity has been restored. Lastly, I demonstrated that pharmacological agonism of MCRs suppresses food intake, overcoming Pomc-deficiency and weight loss, with minimal impact on other motivated behavior.Subjects
POMC Obesity Weight Loss GABA and Glutamate Appetitive Consummatory Behavior
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