Abstract
The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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Acknowledgements
We thank M. Dalman for constructive suggestions, J. Qiu for help in dissection of fat pads, J. McKean for technical assistance and H. Chen for demonstration of implantation of osmotic pumps. E.H.G. is a Howard Hughes Medical Institute (HHMI) Physician Postdoctoral Fellow. This work has been supported by the HHMI and the National Institute of Neurological Disorders and Stroke (L.F.R.).
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Supplementary Fig. 1.
POMC- and AgRP-expressing neurons project to the VMH. (a) POMC neurons and fibers in the hypothalamus. (b) POMC-immunoreactive fibers in the VMH. Arrows indicate fibers with boutons. (c) AgRP-immunoreactive fibers in the hypothalamus. (d) AgRP-immunoreactive fibers in the VMH. Arrows indicate fibers with boutons. Scale bar, (a, c), 50 μm; (b, d), 20 μm. (JPG 30 kb)
Supplementary Fig. 2.
Expression of BDNF is more noticeably reduced in the caudal part of the VMH in an Ay mouse. BDNF expression is revealed with β-galactosidase immunoreactivity in BDNFlacZ/+ mice. Sections in (a) and (b) (approximately Bregma -1.82 mm according to Franklin and Paxinos*), are arbitrarily set as position 0 mm. The relative positions of other sections are indicated. Sections shown here were from a pair of female littermates at 8 weeks of age. Scale bar, 100 μm. (a, c, e, g) BDNF expression in the VMHs of a BDNFlacZ/+ mouse at various caudal-rostral positions. (b, d, f, h) BDNF expression in the VMHs of an Ay/a;BDNFlacZ/+ mouse at various caudal-rostral positions. The areas with apparently reduced BDNF expression in the Ay mouse are outlined. *Franklin, K.B.J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic, San Diego, 1997). (JPG 54 kb)
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Xu, B., Goulding, E., Zang, K. et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat Neurosci 6, 736–742 (2003). https://doi.org/10.1038/nn1073
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DOI: https://doi.org/10.1038/nn1073
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