TLQP-21, a VGF-derived peptide, increases energy expenditure and prevents the early phase of diet-induced obesity

Abstract

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 (...

Chronic intracerebroventricular injection of TLQP-21 prevents high fat diet induced weight gain in fast weight-gaining mice

“…Synthetic TLQP-21 peptide [7] (Primm, Milano, Italy) at the dose of 1 mM dissolved in artificial cerebrospinal fluid (aCSF) or aCSF alone was icv delivered trough Alzet micro-osmotic pumps (Mod. 1002; final volume of 100 ll; flow rate 0.25 ll/h, corresponding to 15 lg/day of TLQP-21) connected to the Alzet brain infusion kit.…”

“…Upon processing by the neuroendocrine-specific prohormone convertases PC1/3 and PC2, VGF may yield a number of peptides that are stored in dense core granules and secreted through regulated pathways [66]. Up to now, six VGFpeptides were shown to modulate with a remarkable peptide-specific selectivity, a diverse range of biological functions such as synaptic plasticity, apoptosis, sexual antidepressant-like behavior and inflammatory pain [2,7,10,11,35,37,58,63,64,65,70].…”

“…Among the different VGF-peptides, however, only the peptide designate TLQP-21 was demonstrated to exert a catabolic role [7,37], while preliminary data showed an orexigenic effect following acute injection of the peptides designated TLQP-62 and HHPD-41 [8]. In particular, Bartolomucci et al [7] proved that chronic icv injection of TLQP-21 increased resting energy expenditure and prevented the early phase of diet-induced obesity and associated leptin and ghrelin alterations.…”

“…In particular, Bartolomucci et al [7] proved that chronic icv injection of TLQP-21 increased resting energy expenditure and prevented the early phase of diet-induced obesity and associated leptin and ghrelin alterations. A later study by Jethwa et al [36,37] demonstrated in hamster an anorectic effect exerted by TLQP-21 which determined a decrease in body weight and adipose fat mass.…”

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

“…Vgf is a component of the chromogranin/secretogranin family 47, 48 actively involved in amyotrophic lateral sclerosis (ALS) neuroprotection 49. Because it is described that declined levels of this bioactive peptide (Vgf) could promote neurodegeneration 50, further investigation of these aspects is required.…”