Food intake and physical activity are coordinately regulated and phased with the female reproductive cycle. While estrogen receptor alpha (ER? in the hypothalamic arcuate nucleus (ARC) modulates food intake, hormone-responsive neurons influencing female locomotion remain undefined. Here, we identify a sexually dimorphic neuronal cluster in the ventromedial hypothalamus (VMH) solely dedicated to promoting physical activity in females. In a loss-of-function study we find that deleting the developmental transcription factor Nkx2-1 with Sf1Cre ablates a subpopulation of ventrolateral VMH neurons expressing ER?and results in marked obesity and reduced locomotion only in these Nkx2- 1Sf1Cre mutant females. Conversely, using a gain-of-function approach we show that directly activating intact Nkx2-1 ventrolateral VMH neurons elicits a female-specific and hormone-dependent burst of physical activity. Loss of gonadal hormone severely blunts this response. Our findings demonstrate that specialized Nkx2-1+ VMH neurons constitute part of a previously undefined sexually dimorphic locomotor circuit that is used specifically in females to combat sedentary behavior and maintain metabolic fitness. Here, we plan to define and understand how this hormone-responsive neural circuit promotes physical activity in females. In three aims, we will 1) assess responses in a different settings to activating DREADDs, 2) determine if estrogen and other potential neuromodulators within VMHvl neurons affect DREADD-induced activity and 3) begin identifying VMHvl markers and mapping projections that are missing/altered in the Nkx2-1Sf1Cre mutant females. Nkx2-1Sf1Cre female mice offer an excellent opportunity to understand the neural basis of gender and hormonal regulation of energy expenditure. Our ultimate goal is to translate this basic research into the development of pharmacological and/or transplantation therapies that can be used to restore metabolic health in females.

Public Health Relevance

Although neural circuits of eating behaviors are defined, little is known about the hormonal- regulation of neural circuits controlling 'physical activity'. Using different mouse models we have discovered a subset of hypothalamic neurons that promote locomotion specifically in females. Here we will ask if this newly identified set of neurons can be manipulated in mice with the aim of eventually targeting sedentary behaviors in women, especially in post-menopausal women.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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University of California San Francisco
Schools of Medicine
San Francisco
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