The vgf gene has been identified as an energy homeostasis regulator. Vgf encodes a 617-aa precursor protein that is processed to yield an incompletely characterized panel of neuropeptides. Until now, it was an unproved assumption that VGF-derived peptides could regulate metabolism. Here, a VGF peptide designated TLQP-21 was identified in rat brain extracts by means of immunoprecipitation, microcapillary liquid chromatography-tandem MS, and database searching algorithms. Chronic intracerebroventricular (i.c.v.) injection of TLQP-21 (15 g͞day for 14 days) increased resting energy expenditure (EE) and rectal temperature in mice. These effects were paralleled by increased epinephrine and up-regulation of brown adipose tissue 2-AR (2 adrenergic receptor) and white adipose tissue (WAT) PPAR-␦ (peroxisome proliferator-activated receptor ␦), 3-AR, and UCP1 (uncoupling protein 1) mRNAs and were independent of locomotor activity and thyroid hormones. Hypothalamic gene expression of orexigenic and anorexigenic neuropeptides was unchanged. Furthermore, in mice that were fed a high-fat diet for 14 days, TLQP-21 prevented the increase in body and WAT weight as well as hormonal changes that are associated with a high-fat regimen. Biochemical and molecular analyses suggest that TLQP-21 exerts its effects by stimulating autonomic activation of adrenal medulla and adipose tissues. In conclusion, we present here the identification in the CNS of a previously uncharacterized VGF-derived peptide and prove that its chronic i.c.v. infusion effected an increase in EE and limited the early phase of diet-induced obesity.autonomic nervous system ͉  adrenergic receptor ͉ MALDI-TOF ͉ neuropeptide ͉ peroxisome proliferator-activated receptor ␦ E nergy homeostasis is a complex physiological function that is coordinated at multiple levels. Stimulated by the discovery of leptin and the pandemic diffusion of obesity and type-2 diabetes, the regulation of energy homeostasis has received increasing attention (1-4). New players are being continuously identified and screened as molecular candidates to counteract obesity (5-10). Vgf, initially identified as a nerve growth factor-responsive gene, is also robustly induced by BDNF and neurotrophin 3 and marginally induced by epidermal and fibroblast growth factors, IL-6, and insulin (11-13). Vgf received great attention after the observation that VGF-deficient mice are lean, hypermetabolic, and resistant to various types of obesity (14, 15). In the rat brain, VGF is abundant in the cortex, hypothalamus, hippocampus, and olfactory system and in a number of thalamic, septal, amygdaloid, and brainstem nuclei, with the local availability of neurotrophins for receptor occupation being the critical parameter in determining its selective expression (12, 13). Changes in vgf expression also increase in the arcuate nucleus of fasted rats (14) and hamsters that are exposed to a short or long day's length (16). However, up until now, it was still unproved that VGF-derived peptides are metabolic neuromodulators (...