The Role of Specific Brain-Derived Neurotrophic Factor (BDNF) Promoters in Obesity

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 685-694-Mechanisms of Obesity
Basic
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-692
Gladys I Palaguachi*1, Dennisse Jimenez2, Dmytro Mikhnev1, Oksana Gavrilova3, Lino Tessarollo4, Bai Lu5, Keri Martinowich2 and Joan C Han1
1National Institutes of Health, Bethesda, MD, 2Maltz Research Laboratories, Baltimore, MD, 3NIH/NIDDK, 4National Institutes of Health, Frederick, MD, 5GlaxoSmithKline, Shanghai, China
Background: Brain-derived neurotrophic factor appears to function downstream of leptin signaling to control energy balance [1]. BDNF expression is driven by multiple 5’ untranslated region (UTR) promoters [2] (with promoters I, II, IV, and VI accounting for the preponderance of transcripts in the hypothalamus [3]), but the individual roles of these promoters in energy regulation remain to be elucidated. Heterozygous Bdnf knock-out mice display hyperphagia and obesity [4-5]. In humans, heterozygous deletion of the first three exons and promoters of BDNF spares the protein coding region for mature BDNF, yet still yields a similarly obese phenotype as haploinsufficiency for the entire BDNF gene [3], suggesting an important role of these early 5’UTR promoters in energy balance. 

Methods: To determine the role of specific Bdnf promoters in energy homeostasis, we studied C57BL/6J mice in which promoters I, IV, or VI have been disrupted by insertion of a GFP-STOP cassette. Body weight was measured weekly in homozygous male Bdnf-I-/-, Bdnf-IV-/-, and Bdnf-VI-/- mice and wild-type (WT) littermates, which were fed ad libitum regular chow diet from weaning. Percent body fat was measured by MRI.

Results: Bdnf-I-/- mice (n=9) compared to WT littermates (n=7) had similar body weight at 8 weeks (mean ± SEM, Bdnf-I-/- vs. WT: 26.0 ± 0.7 vs. 25.7 ± 0.7 g, p=0.82), but significantly higher body weight by 12 weeks (33.8 ± 1.4 vs. 28.5 ± 0.6 g, p=0.009), which was even more pronounced at 6 months (49.4 ± 1.3 vs. 33.6 ± 0.9 g, p<0.0001) and associated with greater percent body fat (30.2 ± 3.2 vs. 16.8 ± 1.9%. p=0.02). In contrast, Bdnf-IV-/- mice (n=9) compared to WT littermates (n=8) had similar body weight at 6 months (Bdnf-IV-/- vs. WT: 34.4 ± 0.7 vs. 32.7 ± 0.6 g, p=0.12). Furthermore, Bdnf-VI-/- mice (n=10) compared to WT littermates (n=10) also had similar body weight at 6 months (Bdnf-VI-/-vs. WT: 29.2 ± 0.6 vs. 30.1 ± 0.4 g, p=0.23).

Conclusions: Mice lacking BDNF protein translated from transcripts driven by Bdnf promoter I had approximately 50% greater body weight and nearly 2-fold higher percent body fat compared to wild-type littermates at 6 months of age, whereas disruption of promoters IV or VI had no significant effect on body weight. Our findings suggest that Bdnf promoter I plays a critical role in regulating energy balance. Further studies are currently underway examining energy intake and expenditure, body composition, biochemical profile, and glucose homeostasis in these mice.

[1] Xu B et al., Nat Neurosci 2003; 6:736. [2] Pruunsild P et al., Genomics 2007; 90:397. [3] Han JC et al., N Engl J Med 2008; 359:918. [4] Kernie SG et al., EMBO J 2000; 19:1290. [5] Lyons WE et al., Proc Natl Acad Sci USA 1999; 96:15239.

Disclosure: BL: Employee, GlaxoSmithKline. Nothing to Disclose: GIP, DJ, DM, OG, LT, KM, JCH

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

Sources of Research Support: Intramural Research Programs of NIMH and Eunice Kennedy Shriver NICHD; NIH Bench-to-Bedside Award.