Uncovering a mechanism for SF-1 transcriptional activation in response to exercise

Ut Southwestern Medical Center, Dallas TX

Investigators

Linked publications, trials & patents

Abstract

PROJECT SUMMARY/ABSTRACT The neurons comprising the ventromedial hypothalamic nucleus (VMH) are critical regulators of energy expenditure and peripheral tissue glucose sensitivity and are essential for metabolic adaptation to challenges such as high fat diet and exercise. The orphan nuclear receptor, Steroidogenic factor 1 (SF-1) is required for both the development of the VMH and for the expression of genes needed for metabolic adaptation. It?s universally known that exercise improves disease outcome apart from simply affecting weight, although how exercise improves neural metabolic regulation is largely unknown. Uncovering the molecular pathways leading to the metabolic improvements seen in exercise, may lead to new treatments to combat metabolic disorders. Recently our lab discovered that brain expression of the orphan nuclear receptor, steroidogenic transcription factor (SF-1) plays a critical role in metabolic improvements resulting from exercise. Exercised mice have increased hypothalamic expression of SF-1 target genes including Bdnf, Cnr1, and Crhr2. Additionally, mice with brain-specific loss of SF-1 show blunted exercise-induced improvements in adiposity, energy expenditure, endurance, fat mobilization, and skeletal muscle adaptation. However it is mechanistically unknown how exercise affect the expression of SF-1 target genes. Give that in adrenal glands, SF-1 transcriptional activity is modified through MAPK-dependent phosphorylation we posit that MAPK may also act in a similar fashion in VMH neurons. Exercise has previously been reported to increase MAPK transcriptional activity in the hypothalamus, however, it is unknown if VMH neurons are among the activated neurons. In this proposal we will use a combination of pharmacological and genetic tools ascertain if exercise induces MAPK-dependent phosphorylation of SF-1 in the VMH. Moreover, we will test if MAPK signaling is required for exercise- dependent gene expression of SF-1 transcriptional targets. Additionally, we will test if exercise affects the binding of SF-1 to the promotor of exercise-response genes. Uncovering the role of exercise-induced ERK signaling in the VMH may lead to new targeted therapies to combat obesity and diabetes.