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.
PROJECT NARRIATIVE Brain expression of the steroidogenic transcription factor (SF-1) is required for many of the metabolic benefits of exercise. The object of this proposal is to identify if exercise activates a MAPK-dependent molecular program within ventromedial hypothalamic (VMH) neurons to alter transcriptional activity of SF-1 target genes. These finding will advance our knowledge of both the neural molecular signaling resulting from exercise and may aid in the development of targeted therapies for obesity related disorders.
| Lord, Caleb C; Wyler, Steven C; Wan, Rong et al. (2017) The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. J Clin Invest 127:3402-3406 |
