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The Journal of Neuroscience, August 15, 2002, 22(16):6929-6938

VGF is Required for Obesity Induced by Diet, Gold Thioglucose Treatment, and Agouti and is Differentially Regulated in Pro-Opiomelanocortin- and Neuropeptide Y-Containing Arcuate Neurons in Response to Fasting

Seung Hahm¹, Csaba Fekete^{3, 5}, Tooru M. Mizuno^{1, 2}, Joan Windsor¹, Hai Yan⁷, Carol N. Boozer⁶, Charlotte Lee⁴, Joel K. Elmquist⁴, Ronald M. Lechan⁵, Charles V. Mobbs^{1, 2}, and Stephen R. J. Salton^{1, 2}

¹ Fishberg Research Center for Neurobiology and ² Department of Geriatrics, Mount Sinai School of Medicine, New York, New York 10029, ³ Department of Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, 1083 Hungary, ⁴ Department of Neurology, Beth Israel Deaconess Medical Center, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02215, ⁵ Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, Tupper Research Institute and Department of Medicine, New England Medical Center, Boston, Massachusetts 02111, ⁶ Obesity Research Center, St. Luke's-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, New York 10025, and ⁷ Amgen Inc., Thousand Oaks, California 91320

Targeted deletion of the gene encoding the neuronal and neuroendocrine secreted polypeptide VGF (nonacronymic) produces a lean, hypermetabolic mouse. Consistent with this phenotype, VGF mRNA levels are regulated in the hypothalamic arcuate nucleus in response to fasting. To gain insight into the site(s) and mechanism(s) of action of VGF, we further characterized VGF expression in the hypothalamus. Double-label studies indicated that VGF and pro-opiomelanocortin were coexpressed in lateral arcuate neurons in the fed state, and that VGF expression was induced after fasting in medial arcuate neurons that synthesize neuropeptide Y (NPY). Like NPY, VGF mRNA induction in this region of the hypothalamus in fasted mice was inhibited by exogenous leptin. In leptin-deficient ob/ob and receptor-mutant db/db mice, VGF mRNA levels in the medial arcuate were elevated. To identify neural pathways that are functionally compromised by Vgf ablation, VGF mutant mice were crossed with obese A^y/a (agouti) and ob/ob mice. VGF deficiency completely blocked the development of obesity in A^y/a mice, whereas deletion of Vgf in ob/ob mice attenuated weight gain but had no impact on adiposity. Hypothalamic levels of NPY and agouti-related polypeptide mRNAs in both double-mutant lines were dramatically elevated 10- to 15-fold above those of wild-type mice. VGF-deficient mice were also found to resist diet- and gold thioglucose-induced obesity. These data and the susceptibility of VGF mutant mice to monosodium glutamate-induced obesity are consistent with a role for VGF in outflow pathways, downstream of hypothalamic and/or brainstem melanocortin 4 receptors, that project via the autonomic nervous system to peripheral metabolic tissues and regulate energy homeostasis.

Key words: VGF; neurotrophin; hypothalamus; obesity; agouti; POMC; NPY; leptin; melanocortin

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22166929-10$05.00/0

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