Obesity is recognized as a major health issue due to its high prevalence and strong association with diabetes and other metabolic disorders. Female animals are more resistant to obesity than males, but the mechanisms for this sexual dimorphism remain elusive. In my previous studies, I first screened body weight-regulatory neural populations and found that pro-opiomelanocortin (POMC) neurons in female mice fire more rapidly than male POMC neurons, and female mouse brains express higher POMC transcripts. Further, these sex differences in POMC neurons were associated with higher expression levels of TAp63 (a transcription factor) and SRC1 (steroid receptor coactivator-1, a transcriptional coactivator) in female POMC neurons than in male counterparts. Pilot studies showed that TAp63 can activate POMC gene expression in cultured cells. Further, SRC1 mRNA was significantly reduced by TAp63 deletion in female mice, suggesting that SRC1 is a transcription target of TAp63. Importantly, deletion of TAp63 or SRC1 only in POMC neurons in mice regulates body weight in a sexually dimorphic fashion. Together, I developed a hypothesis that an estrogen-TAp63-SRC1 transcriptional axis contributes to the sexual dimorphism in POMC neuron functions and energy homeostasis. I will generate mice that lack TAp63 or SRC1 in POMC neurons, and characterize energy homeostasis and POMC neuron functions (activity and gene expression profile) among male mice, female mice with or without intact ovary (OVX- V), and female without intact ovary but with estrogen supplement (OVX-E). I will also examine whether estrogen stimulates TAp63 expression and whether TAp63 stimulates SRC1 expression. The proposed studies represent logical extensions to my previous work, and will advance our understanding about the fundamental biology for sex differences in body weight control, which may facilitate the development of gender-specific therapeutic strategies for obesity and associated metabolic diseases. In addition, this project will provide an ideal training opportunity to prepare me for an independent research career focusing on transcriptional mechanisms in the hypothalamus and their roles in metabolic control.
Obesity has been recognized as a global epidemic, strongly associated with metabolic disorders, and females are more resistant to diet-induced obesity than males. To explore the mechanisms for sex differences in body weight control, I will test whether and how an estrogen-TAp63-SRC1 transcriptional axis contributes to the sexual dimorphism in POMC neuron functions and energy homeostasis. These studies will advance our understanding about the fundamental biology for sex differences in body weight control, and may facilitate the development of gender- specific therapeutic strategies for obesity and associated metabolic diseases.
