Neuroanatomical substrates underpinning brain aromatase control of feeding behavior and metabolic homeostasis

Project Summary Estradiol orchestrates feeding behavior and metabolism. Aromatase is the sole enzyme responsible for producing estradiols from androgens, and it is highly expressed in gonads. In humans and rodents, neurons in discrete brain regions densely express aromatase. The role of brain aromatase and locally de novo (brain)- derived estradiols in energy balance control remains poorly understood. Our goal is to provide answers for several pressing basic questions: – is brain-aromatase necessary for feeding and energy balance control? Is the role of brain aromatase neuroanatomically and sex divergent? How do brain and gonadal aromatase interact in metabolic control? We identified two populations of aromatase-expressing neurons, in the central nucleus of the amygdala (CeA) and in the ventromedial hypothalamus (VMH), in female and male rats. Our preliminary data suggest aromatase specifically in the CeA controls feeding behavior and subsequent weight gain in a sex- specific manner. In contrast, aromatase in the VMH, exerts control over the brown adipose tissue thermogenic capacity and response, in both sexes. Therefore, in this project we will pursue the hypothesis that aromatase in the CeA is critical to feeding behavior control in a sex-selective manner, while aromatase action in the VMH has the primary role of energy expenditure control in both males and females. We further posit that aromatase in the VMH, but not CeA, may be particularly important under conditions of metabolic challenges and pathophysiology. The proposed studies combine behavioral, metabolic, neuroanatomical, molecular, and virogenetic strategies in adult rats to support or refute this hypothesis by conducting detailed mechanistic experiments organized in two aims. In Aim I we strive to identify the specific contribution to feeding control and downstream mechanisms orchestrated by amygdala aromatase. Here we will resolve whether CeA aromatase is necessary and sufficient to control food-motivated and ingestive behavior. We will determine whether local, intra-amygdala, and distal, lateral hypothalamic sex-specific pathways are engaged by CeA aromatase neurons, and whether loss of this input leads to disinhibition of hypothalamic orexigenic pathways. The specific broad goal of Aim II is to test whether hypothalamic aromatase controls feeding and thermoregulation under normal and metabolically challenging conditions. We will examine whether aromatase in the VMH is necessary and sufficient for energy expenditure and body weight control in both sexes. Experiments here are also designed to reveal whether VMH aromatase has a critical role in adaptation to metabolic challenges: obesogenic diet and cold exposure, in both sexes. Finally, and in contrast to CeA, we hypothesize that VMH aromatase and resulting estradiol are responsive to and work in concert with gonadal steroids. If our hypothesis is supported, we will show that brain aromatase and resulting locally produced estradiols are key to maintenance of energy balance during metabolic health and disease.