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Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor

Nature Neuroscience volume 6, pages 736–742 (2003)Cite this article

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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Figure 1: Energy status regulates levels of BDNF in the VMH.
Figure 2: Coexpression of TrkB and neuropeptides in the hypothalamus.
Figure 3: The trkB hypomorphic mutant shows maturity-onset obesity and increased linear growth.
Figure 4: Hyperphagia and hyperdipsia of the trkB hypomorphic mutant mice.
Figure 5: Melanocortins regulate the levels of BDNF mRNAs in the VMH.
Figure 6: Melanocortins regulate expression of BDNF in selective populations of neurons in the VMH.
Figure 7: TrkB acts downstream of MC4R to regulate feeding response to dietary fat.

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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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Author notes

  1. Baoji Xu

    Present address: Department of Pharmacology, Georgetown University Medical Center, SE402 Medical/Dental Building, 3900 Reservoir Rd. NW, Washington, DC, 20057, USA

Authors and Affiliations

  1. Howard Hughes Medical Institute, University of California, San Francisco, 94143, California, USA

    Baoji Xu, Keling Zang & Louis F Reichardt

  2. Center for Neurobiology and Psychiatry, University of California, San Francisco, 94143, California, USA

    Evan H Goulding & Laurence H Tecott

  3. Vollum Institute, Oregon Health and Science University, Portland, 97201, Oregon, USA

    David Cepoi & Roger D Cone

  4. Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, 80309, Colorado, USA

    Kevin R Jones

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Supplementary information

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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