The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.

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 (...

To throw light onto the mechanism(s) by which the cholinergic system influences growth hormone (GH) release, the effects of two muscarinic receptor blockers, pirenzepine and atropine, and of an acetylcholinesterase inhibitor, pyridostigmine bromide, on the GH response to GHRH-44 were studied in 19 normal volunteers. Moreover, the effects of pirenzepine administration on plasma GH levels both in basal conditions and after stimulation by GHRH-44 and TRH were studied in 9 acromegalics. Both pirenzepine (0.6 mg/kg i.v., 5 min before GHRH) and atropine (1 mg i.m., 15 min before GHRH) blunted the GH response to GHRH (1 µg/kg i.v. bolus) (area under the response curve, AUC: 81.3 ± 17.3 vs. 481.2 + 211.3 ng/ml/h for pirenzepine and 100.2 ± 27.0 vs. 364.7 + 81.0 ng/ml/h for atropine; p < 0.01). Pyridostigmine (120 mg orally, 30 min before GHRH) induced a variable but significant (p < 0.02) rise in basal plasma GH levels and, furthermore, an unequivocal potentiation of the GH response to GHRH (AUC: 1044.6 + 245.3 vs. 481.2 + 211.3 ng/ml/h; p

Abstract. It is known that in normal subjects repeated administrations of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 μg iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.