Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance

To determine the function of VGF, a secreted polypeptide that is synthesize d by neurons, is abundant in the hypothalamus, and is regulated in the brai n by electrical activity, injury, and the circadian clock, we generated kno ckout mice lacking Vgf. Homozygous mutants are small, hypermetabolic, hyper active, and infertile, with markedly reduced leptin levels and fat stores a nd altered hypothalamic proopiomelanocortin (POMC), neuropeptide Y (NPY), a nd agouti-related peptide (AGRP) expression. Furthermore, VGF mRNA synthesi s is induced in the hypothalamic arcuate nuclei of fasted normal mice. VGF therefore plays a critical role in the regulation of energy homeostasis, su ggesting that the study of lean VGF mutant mice may provide insight into wa sting disorders and, moreover, that pharmacological antagonism of VGF actio n(s) might constitute the basis for treatment of obesity.