Author

Bora Lee

Date

12-2015

Document Type

Thesis

Degree Name

Ph.D.

Department

Department of Cell & Developmental Biology

Abstract

We have witnessed a dramatic expansion of metabolic pathologies including obesity, diabetes, and cardiovascular diseases during the last several decades. The fundamental cause of obesity and many metabolic disorders is an energy imbalance between caloric input and energy output. The hypothalamic arcuate nucleus harbors several types of neurons that are crucial for controlling energy balance by sensing and translating various peripheral cues into the central nervous system action. Among these neurons, agouti-related peptide (AgRP) neurons and proopiomelanocortin (POMC) neurons regulate energy balance by producing orexigenic neuropeptides, AgRP and neuropeptide Y (NPY), and anorexigenic neuropeptide αMSH, respectively. Despite great advances in characterizing the physiological roles of these neurons, the molecular basis underlying how these neurons develop and function at later postnatal stages is still poorly understood. Here we present our discoveries that reveal two key molecular mechanisms for how the expression of the orexigenic neuropeptides, AgRP and NPY, are controlled, and also identify a critical transcription factor (Isl1) that regulates embryonic development of various arcuate neuronal cell types.

First, I present a novel glucocorticoid response element (GRE) in the AgRP promoter region (AgRP-GRE). The unique sequence of this GRE enables glucocorticoid receptor (GR) and brain-specific homeobox factor (Bsx) to synergize for the direct transactivation of the gene encoding the orexigenic neuropeptide AgRP. During fasting, both blood glucocorticoid level and Bsx expression in AgRP neurons are increased. In turn, ligand bound GR is translocated to the nucleus where it interacts with Bsx and binds to AgRP-GRE to activate AgRP expression. In contrast to AgRP-GRE, Bsx suppresses transactivation mediated by many conventional GREs and functions as a gene context dependent modulator of GR actions. These results provide an opportunity to identify novel common targets of GR and Bsx and to bette understand the molecular basis underlying the orexigenic activityo glucocorticoid and Bsx.

Second, I present a new gene regulatory network involving GR and another nuclear hormone receptor, neuron-derived orphan receptor-1 (NOR1) which regulates the expression of AgRP and NPY in response to periphera signals. The anorexigenic signal leptin induces NOR1 expression via the transcription factor cAMP response element binding protein (CREB) while the glucocorticoid bound GR inhibits NOR1 expression by antagonizing the action o CREB on NOR1 expression. Conversely, NOR1 suppresses glucocorticoid dependent activation of AgRP. It appears that mutual antagonism between NOR1 and GR is critical for detecting peripheral metabolic signals and fo modulating gene expression in the arcuate nucleus to centrally regulate energy balance.

Lastly, I show that the LIM-homeodomain transcription factor Islet1 (Isl1 plays a critical role in fate specification of several developing arcuate neurons.

The loss of Isl1 in the developing hypothalamus results in striking deficits in both feeding and linear growth. In line with these phenotypes, expression of the orexigenic neuropeptides AgRP, NPY, growth hormone-releasing hormone (GHRH) and somatostatin (SST), which represent the key identity markers o feeding and growth controlling arcuate neurons, is completely abolished by the loss of Isl1. Finally, Isl1 directly regulates AgRP expression by cooperating with GR and Bsx.

Collectively, this dissertation identifies several critical gene regulatory mechanisms in hypothalamic arcuate neurons during development and postnata energy balance function.

Identifier

doi:10.6083/M4Z03767

School

School of Medicine

Available for download on Thursday, April 18, 2019

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