DOI

10.17077/etd.emlingwx

Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Neuroscience

First Advisor

Sigmund, Curt D.

Second Advisor

Rahmouni, Kamal

First Committee Member

Weiner, Joshua

Second Committee Member

Norris, Andrew

Third Committee Member

Grobe, Justin

Abstract

The Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a master regulator of adipogenesis, has been shown to influence energy balance through its actions in the brain rather than in the adipose tissue alone. Deletion of PPARγ in mouse brain results in resistance to weight gain in response to high fat diet. Activation of PPARγ leads to change in the firing pattern of melanocortin system neurons (POMC and AgRP), which are critical for energy homeostasis. To determine the effects of modulation of brain PPARγ on food intake and energy expenditure we generated a novel transgenic mouse model in which a dominant-negative (DN) mutant form of PPARγ (P467L) or a wild type (WT) form that is conditionally expressed in either the entire central nervous system (CNS) or specifically in POMC or AgRP neurons. Interference with brain PPARγ results in impaired insulin and glucose regulation. This in turn has significant implications in altering the growth rate and metabolic homeostasis. In light of the well-established role of PPARγ in regulating insulin sensitivity, this is the first report implicating brain PPARγ in controlling peripheral insulin levels. Overexpression of the WT PPARγ in the CNS leads to failure to thrive and early death due to microcephaly and severe distortion of brain architecture with notable agenesis of the corpus callosum. Our results show that the levels of PPARγ in the brain are tightly regulated and perturbations leading to “too much” or “too little” functional PPARγ result in major shifts in structural organization of the brain or metabolic balance.

The herein presented data show that chronic interference with the function of neuronal PPARγ affects energy balance only under certain dietary conditions and through specific neuronal populations. We show that POMC, but not AgRP neurons, are particularly sensitive to modulation of PPARγ activity. These observations give support to the notion that cellular adaptations in POMC neurons, driven by PPARγ, represent critical components in the regulation of metabolic homeostasis.

Pages

xii, 168 pages

Bibliography

Includes bibliographical references (pages 148-168).

Copyright

Copyright © 2017 Madeliene Stump

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