OR08-2 A Population of Nkx2-1 Neurons in the Ventromedial Hypothalamus (VMH) Mediates Sex-Specific Obesity and Sedentary Behavior in Mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR08-Obesity: Novel Mechanisms of Body Weight Regulation
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:45 AM
Room 301 (Moscone Center)
Stephanie M Correa*1, David W Newstrom1, Clement C Cheung1, James Philip Warne1, Pierre Flandin2, Andrew A Pierce3, Allison Xu1, John L Rubenstein2 and Holly A Ingraham1
1University of California San Francisco, San Francisco, CA, 2University of California San Francisco, 3University of California San Francisco, CA
The ventromedial hypothalamus (VMH) plays important roles in reproduction, anxiety, aggression, ingestive behavior, and energy expenditure.  Nkx2-1 (Ttf-1) is a homeobox transcription factor that is expressed in hypothalamic progenitors beginning at embryonic day 9 and persists in adult VMH neurons.  Sf1 (Nr5a1) is one of the earliest markers of VMH neurons and its expression overlaps with Nkx2-1 only in the VMH.  To determine Nkx2-1 function in VMH neurons, we conditionally ablated Nkx2-1 in the developing VMH using Sf1-driven CRE recombinase (Nkx2-1Sf1Cre).  We and found that female mutant mice were significantly heavier than control littermates when fed normal chow.  In contrast, body weights of male mutants were normal.  Increased body weight in Nkx2-1Sf1Cre females was attributed to higher body fat deposition in visceral and subcutaneous depots but no changes in brown fat mass or thermogenesis.  Metabolic analyses revealed that obesity in Nkx2-1Sf1Cre females was due to reduced energy expenditure rather than increased food intake; Nkx2-1Sf1Cre females exhibit a specific deficit in locomotor activity.  Expression analyses of Nkx2-1Sf1Cre female VMH revealed a significant and selective decrease of NKX2-1 and ERa in the ventrolateral VMH (VMHvl), whereas NKX2-1 and ERa were unchanged in the neighboring arcuate nucleus.  Despite the loss of ERa expression in the VMH, female Nkx2-1 Sf1Cre mice exhibited normal fertility.  To further demonstrate that Nkx2-1 neurons in the VMHvl regulate physical activity, we performed pharmacogenetic experiments using Designer Receptors Activated by Designer Drugs (DREADDs).  Artificially activating Nkx2-1 neurons in the VMHvl of Nkx2-1Cre female mice resulted in higher VO2 consumption and increased movement, demonstrating that these specialized VMH neurons regulate physical activity.  We propose that estrogen-responsive Nkx2-1 neurons in the VMH regulate physical activity in female mice and that loss of these neurons underlies the “couch-potato” phenotype observed in mutant females.  If successful, research efforts to define this unique population of hypothalamic neurons should provide new potential strategies for decreasing sedentary behavior and improving metabolic health in women.

Nothing to Disclose: SMC, DWN, CCC, JPW, PF, AAP, AX, JLR, HAI

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH Grant DK063592 and UCSF Diabetes Family Fund Grant awarded to HAI; American Heart Association Postdoctoral Fellowship awarded to SMC