Document Type
Article
Publication Date
12-2003
Abstract
The fact that the proopiomelanocortin (POMC) gene is a critical component of energy homeostasis and the stress response, two distinct yet not exclusively separate biological functions, distinguishes this gene as very intriguing and unique for st lllldy. The POMC gene encodes a preprohormone that is post-translationally processed into multiple bioactive peptides. The tissue specific regulation and tissue specific post-translational modifications provide a means for the broad spectrum of the gene's biological activities. Understanding the POMC gene's cell-specific regulation and the physiological functions of its encoded peptides has been an ongoing project of multiple labs spanning the last two decades. Initial studies predominately revolved around the role of the POMC peptide adrenocorticotropin-stimulating hormone's (ACTH) function as a key descending-component of the hypothalamicpituitary adrenal axis. Recently, the majority of studies have transitioned to a focus on the hypothalamic POMC peptide, a.-MSH, and its anorexigenic effects. This focus is with good reason. Within affluent societies, the rampant increase in obesity and overweight prevalence and the associated risk for several chronic diseases has accentuated the need for understanding the biological mechanisms of energy homeostasis. Using the murine rodent for its genetic advantages, this thesis attempts to further advance our understanding of the POMC system regarding its gene expression, neuron physiology, and biological functions.
The fact that the proopiomelanocortin (POMC) gene is a critical component of energy homeostasis and the stress response, two distinct yet not exclusively separate biological functions, distinguishes this gene as very intriguing and unique for st lllldy. The POMC gene encodes a preprohormone that is post-translationally processed into multiple bioactive peptides. The tissue specific regulation and tissue specific post-translational modifications provide a means for the broad spectrum of the gene's biological activities. Understanding the POMC gene's cell-specific regulation and the physiological functions of its encoded peptides has been an ongoing project of multiple labs spanning the last two decades. Initial studies predominately revolved around the role of the POMC peptide adrenocorticotropin-stimulating hormone's (ACTH) function as a key descending-component of the hypothalamicpituitary adrenal axis. Recently, the majority of studies have transitioned to a focus on the hypothalamic POMC peptide, a.-MSH, and its anorexigenic effects. This focus is with good reason. Within affluent societies, the rampant increase in obesity and overweight prevalence and the associated risk for several chronic diseases has accentuated the need for understanding the biological mechanisms of energy homeostasis. Using the murine rodent for its genetic advantages, this thesis attempts to further advance our understanding of the POMC system regarding its gene expression, neuron physiology, and biological functions.
Whether the hypothalamic POMC peptides have functions that are exclusive to hypothalamic neurons or whether pituitary POMC cells provide a redundancy for these hypothalamic neurons was not known. Utilizing promoter-mapping data, we generated a transgene that would selectively rescue pituitary POMC while retaining the neuronal POMC deficiency when crossed onto a POMC null mutant that we obtained from the Hochgeschwender laboratory. Our studies revealed that replacing pituitary POMC (Pomc_1 _; Tg/+) was not sufficient to rescue the phenotypes caused by the ubiquitous absence of POMC peptides in the Pomc_,_ mice. In fact some of the phenotypes present in the Pomc_,_ mouse, such as obesity and diabetes, were accentuated in the mice lacking only CNS POMC. Obesity in the Pomc_,_ mice resulted from a decrease in their basal metabolic rate (BMR). Replacing pituitary POMC and thus glucocorticoids resulted in a further depression in the mouse's BMR. Replacing pituitary POMC did not normalize the HPA axis but instead further suggested a regulation of the HP A axis, independent of glucocorticoids, by hypothalamic POMC neurons. The lack of CRH suppression in the presence of elevated circulating corticosterone in the Pomc-1 -; Tgl+ mice lead us to the previous conclusion. CRH is a known anorexigenic peptide and evidence supporting the opposing regulation of these neurons by POMC peptides, a-MSH and P-endorphin, makes this hypothalamic circuitry very intriguing for not only future stress axis studies but energy homeostasis studies as well.
Recommended Citation
Smart, James L., "Proopiomelanocortin Physiological Roles: Pituitary Versus Hypathalamic Functions" (2003). Faculty Publications - Department of Biological & Molecular Science. 109.
https://digitalcommons.georgefox.edu/bio_fac/109
Comments
Presented to the Neuroscience Degree Granting Program and the Oregon Health and Science University School of Medicine in partial fulfillment of the requirements for the degree of Doctorate of Philosophy December 2003.