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 (...
The low-affinity p75 neurotrophin receptor is believed to participate with the Trk receptor tyrosine kinase in the formation of high-affinity binding sites for nerve growth factor (NGF). resulted in mutant mice with dramatic sensory deficiencies, such as heat insensitivity (18), indicating that p75 plays an essential role in NGF function.Both p75 and pl40trk are coexpressed in vivo in the majority of NGF-responsive neuronal populations, such as sensory and sympathetic neurons, and cholinergic neurons in the basal forebrain (19-21). An essential question that arises is why neurotrophins interact with these two distinct receptor molecules. We have approached this question by studying a mutant PC12 rat pheochromocytoma cell line which is highly deficient in wild-type p75. These cells express a truncated receptor carrying the transmembrane and cytoplasmic domains of p75. Here we report that these cells display striking differences in high-affinity binding and responsiveness toward related neurotrophin factors. MATERIALS AND METHODSCells and Reagents. PC12 cells were cotransfected on 100-mm dishes with the mR plasmid and pSV2neo at a 10:1 ratio by the Lipofectin procedure (BRL). Independent clones were isolated after growth and selection with the neomycin analogue G418 (GIBCO) at 0.5 mg/ml. Antiserum to NGF was from Collaborative Research. NGF was from Bioproducts for Science (Indianapolis), and NT-3 was a gift from Chiron.125I-labeled NGF was prepared by lactoperoxidase treatment and used within 10 days. Crosslinking reactions with 3-ethyl-1-(3-dimethylaminopropyl)carbodiimide (EDAC, Pierce) and disuccinimidyl suberate (DSS, Pierce) were carried out as described (11,22,23
Nerve growth factor (NGF) is essential for the development and differentiation of sympathetic or sensory neurons. A complementary DNA was cloned that corresponds to a gene sequence induced more than 50-fold in a cultured target cell line of pheochromocytoma cells (PC12 cells) 5 hours after the addition of NGF. The induced messenger RNA encodes a 90,000-dalton polypeptide that may represent one of the primary events in NGF-induced differentiation of neurons.
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