Holly Ingraham, PhD

Neural Basis for Sex-Differences in Metabolism

In women, the loss of estrogen correlates with increased risk for obesity, diabetes and bone fractures. Hence, the precipitous drop in hormone replacement therapy in the last decade, coupled with longer lifespans suggests that the risk for metabolic diseases will continue to rise for the large number of post-menopausal women in the U.S. Nearly all studies on estrogen signaling in females have focused on peripheral systems. In our lab, we are taking a different approach and asking how central estrogen signaling in the hypothalamus contributes to physiological endpoints in females. 

We use a discovery-based approach to define the physiological and genomic consequences of hypothalamic ERa signaling in the mediobasal hypothalamus (MBH). We are currently focused on two regions, the ventrolateral ventromedial hypothalamus (VMHvl) and the arcuate (ARC); both of these regions express much higher levels of the primary estrogen receptor (ERa) in the female brain. Our published and unpublished work shows that these two well-defined MBH regions integrate estrogen signaling to coordinate metabolic, bone physiology and reproductive physiology. Estrogen signaling in the VMHvl controls both locomotion and adaptive thermogenesis in female mice. Estrogen signaling in the ARC has a surprising role - it does not control food intake but does appear to be critical for bone physiology. We are using a variety of techniques to pinpoint which subset of neurons control these functions using transcriptional, translational, and metabolic profiling. We also want to understand the underlying basis for the large sex-differences and functions mediated by MBH neurons. 

Current Projects

To date, assessing the role of central estrogen signaling has generally been limited to standard endpoints, such as fertility, food intake, weight gain on HFD, oxygen consumption, locomotion, etc. We believe there is a compelling need to go beyond these assays to better understand the role of central estrogen signaling in metabolism and reproduction. As such we now use viral delivery of Cre to acutely knock-out ERa as well as activating and inhibitory DREADDs to manipulate ERa neurons in different regions of the MBH. Our assays include the use of a new female Thermo Mouse for real in vivo imaging of BAT activity as well as micro-CT for imaging of bone density. Eventually we want to understand how estrogen modulates neuronal activity.

Lab Members

Lab Website