Role of the kidney in regulating plasma immunoreactive beta-melanocyte-stimulating hormone.

An analysis of the factors that influence the increase in plasma immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) concentration in chronic renal failure showed that: (a) the increase correlated with the increase in serum creatinine concentrations; (b) beta-MSH was not cleared from the plasma by haemodialysis; (c) beta-MSH concentrations increased with length of time on dialysis and increased further after bilateral nephrectomy but there was no further increase with time; (d) beta-MSH levels decreased to normal after renal transplantation; and (e) beta-MSH was excreted in urine only when plasma levels rose to well above those of chronic renal failure (in Nelson''s syndrome). These findings suggest that the kidney regulated plasma beta-MSH by a non-excretory mechanism and is the major site of beta-MSH metabolism.     

Potent peptide agonists for human melanocortin 3 and 4 receptors derived from enzymatic cleavages of human beta-MSH(5-22) by dipeptidyl peptidase I and dipeptidyl peptidase IV

Human beta-MSH(1-22) was first isolated from human pituitary as a 22-amino acid (aa) peptide derived from a precursor protein, pro-opiomelanocortin (POMC). However, Bertagna et al. demonstrated that a shorter human beta-MSH(5-22), (DEGPYRMEHFRWGSPPKD), is a true endogenous peptide produced in human hypothalamus. In this report, we demonstrated that in vitro enzymatic cleavage of native human beta-MSH(5-22) with two ubiquitous dipeptidyl peptidases (DPP), DPP-I and DPP-IV, generated two potent MC3/4R peptide analogues, beta-MSH(7-22) (GPYRMEHFRWGSPPKD) and beta-MSH(9-22) (YRMEHFRWGSPPKD). In fact, the MC4R binding affinity and functional potency of beta-MSH(7-22) (Ki=4.6 nM, EC50=0.6 nM) and beta-MSH(9-22) (Ki=5.7 nM, EC50=0.6 nM) are almost an order of magnitude greater than those of their parent peptide, beta-MSH(5-22) (MC4R, Ki=23 nM, EC50= 3nM). Furthermore, the DPP-I/DPP-IV cleaved peptide, beta-MSH(9-22), when administered intracerebroventricularly (ICV) at a dose of 3 nmol/rat, potently induced an acute negative energy balance in a diet-induced obese rat model, while its parent molecule, beta-MSH(5-22), administered at the same dose did not have any effect. These data suggest that DPP-I and DPP-IV may play a role in converting the endogenous beta-MSH(5-22) to more potent peptides that regulate energy homeostasis in the hypothalamus.     

beta-MSH: a functional ligand that regulated energy homeostasis via hypothalamic MC4-R?

alpha-Melanocyte stimulating hormone (MSH) has generally been assumed to be the endogenous ligand acting at the melanocortin-4 receptor (MC4-R), activation of which in the hypothalamus leads to reduced feeding. However, beta-MSH is also capable of activating MC4-R and inhibiting feeding. Here, we investigated the possibility that beta-MSH acts as an endogenous MC4-R agonist and that this melanocortin peptide plays a role in the regulation of feeding and energy balance. We found that beta-MSH had significantly higher affinities than alpha-MSH at both human MC4-R transfected into CHO cells (K(i): beta-MSH, 11.4+/-0.4 nmol/l versus alpha-MSH, 324+/-16 nmol/l, P<0.001) and MC4-R in rat hypothalamic homogenates (K(i): beta-MSH, 5.0+/-0.4 nmol/l versus alpha-MSH, 22.5+/-2.3 nmol/l, P<0.001). Incubation of brain slices with 5 microM beta-MSH significantly increased [35S]GTPgammaS binding by 140-160% (P<0.001), indicating activation of G-protein-coupled receptors (GPCRs), in the hypothalamic ventromedial (VMH), dorsomedial (DMH), arcuate (ARC) and paraventricular (PVN) nuclei. These sites match the distribution of beta-MSH immunoreactive fibres and also the distribution of MC4-R binding sites which we and others previously reported. Food-restriction significantly increased beta-MSH levels in the VMH, DMH and ARC (all P<0.05) above freely-fed controls, whilst alpha-MSH concentrations were unchanged. We propose that increased beta-MSH concentrations reflect blockade of the peptide's release in these sites, consistent with the increased hunger and the known up-regulation of MC4-R in the same nuclei. Thus, we conclude that (1). beta-MSH has higher affinity at MC4-R than alpha-MSH; (2). beta-MSH activates GPCR in these sites, which are rich in MC4-R; and (3). beta-MSH is present in hypothalamic nuclei that regulate feeding and its concentrations alter with nutritional state. We suggest that beta-MSH rather than alpha-MSH is the key ligand at the MC4-R populations that regulate feeding, and that inhibition of tonic release of beta-MSH is one mechanism contributing to hunger in under-feeding.     

Sites of action of beta-melanocyte stimulating hormone in aldosterone biosynthesis in the rat

The sites of action of beta-melanocyte stimulating hormone (beta-MSH) on aldosterone biosynthesis were studied using collagenase-dispersed adrenal glomerulosa cells from rats maintained on either normal or sodium-deficient diets for 2 weeks. Isolated cells were treated with a cyanoketone derivative (WIN 19,578) to isolate the early and late steps in aldosterone biosynthesis. WIN 19,578 (1 microM) completely blocked aldosterone production stimulated by sodium depletion, AII, ACTH, and beta-MSH. beta-MSH (1 microM) significantly stimulated pregnenolone production (early step) and the conversion of corticosterone to aldosterone (late step) in aldosterone biosynthesis. The effect of beta-MSH was similar to AII and ACTH. Sodium depletion enhanced the effect of beta-MSH only on the late step in aldosterone biosynthesis. In conclusion, beta-MSH stimulates both the early and late steps of aldosterone biosynthesis. These results suggest that beta-MSH or peptides containing beta-MSH may play a role in the regulation of aldosterone production.     

Melanotropins: aldosterone- and corticosterone-stimulating activity in isolated rat adrenal cells

Stimulation of corticosterone and aldosterone production in rat adrenal decapsular and capsular cells respectively by alpha- and beta-melanotropins (alpha- and beta-MSH) have been investigated. Although they are considerably less potent than corticotropin (ACTH), the dose-response curves are parallel to those for ACTH except in the case of aldosterone stimulation by beta-MSH where the dose-response curve is biphasic. The steroidogenic actions of ACTH, beta-MSH and alpha-MSH are antagonized by corticotropin-inhibiting peptide in both capsular and decapsular cells. A synthetic analog of beta-MSH ([Gly10]-betac1-MSH) inhibits both beta-MSH and ACTH in aldosterone output in capsular cells, but it does not inhibit their corticosteroidogenic actions in decapsular cells.     

Immunoreactive beta-melanocyte-stimulating hormone in cerebrospinal fluid and plasma in hypopituitarism: evidence for an extrapituitary origin.

Immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) was measured in the plasma of 19 patients with hypopituitarism and in the cerebrospinal fluid (CSF) of five of these patients. In neither plasma nor CSF were the beta-MSH concentrations significantly different from those in normal controls. These observations raise the possibility that beta-MSH may be produced by and secreted from neural tissue; this is supported by the findings of beta-MSH in high concentrations in many parts of the brain.     

Melanotropic activity of gamma MSH peptides in melanoma cells.

We studied the pigmentary activity of the peptides gamma 1, gamma 2 and gamma 3 melanocyte stimulating hormone (MSH), which differ in the structure of their C-termini, using hamster and mouse melanoma cell lines responsive to beta-MSH by increasing tyrosinase activity. Gamma 1-MSH alone or in combination with beta-MSH had no effect on either cell line. Gamma 2-MSH alone was biologically inactive but potentiated beta-MSH stimulation of tyrosinase activity. Gamma 3-MSH at high concentration (10 microM) induced tyrosinase activity and dendrite formation in the hamster melanoma line. When added together with beta-MSH, gamma 3-MSH partially inhibited the tyrosinase activity response to beta-MSH. Thus, gamma-MSH peptides have low intrinsic melanotropic activity in mammalian melanoma cells; the specific pigmentary responses appear to be affected by the structure of the C-terminal portion.     

A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance

The melanocortin-4 receptor (MC4R) plays a critical role in the control of energy balance. Of its two pro-opiomelanocortin (POMC)-derived ligands, alpha- and beta-MSH, the majority of attention has focused on alpha-MSH, partly reflecting the absence of beta-MSH in rodents. We screened the POMC gene in 538 patients with severe, early-onset obesity and identified five unrelated probands who were heterozygous for a rare missense variant in the region encoding beta-MSH, Tyr221Cys. This frequency was significantly increased (p < 0.001) compared to the general UK Caucasian population and the variant cosegregated with obesity/overweight in affected family members. Compared to wild-type beta-MSH, the variant peptide was impaired in its ability to bind to and activate signaling from the MC4R. Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis.     

In vitro biosynthesis of gamma-lipotropic hormone.

Sheep gamma-lipotropic hormone (gamma-LPH) is a pituitary polypeptide made of 58 amino acids and is formed of the first 58 residues of beta-lipotropic hormone (beta-LPH). The C-terminal portion (41-58) of gamma-LPH is identical with the structure of beta-melanophore-stimulating hormone (beta-MSH). We hypothetized in 1967 that beta-LPH could be the biological precursor of beta-MSH and that gamma-LPH could be an intermediate compound. We demonstrated in 1974 that beta-LPH is actively synthesized in the bovine pituitaries. We now studied the biosynthesis of gamma-LPH by monitoring the incorporation of radioactive amino acids in beef pituitary slices. We separated gamma-LPH from the other radioactive proteins with a method previously described. We characterized the radioactive proteins by ion-exchange chromatography, gel filtration and polyacrylamide gel electrophoresis. Our results show that radioactive gamma-LPH was actively synthesized. This gamma-LPH has all the chemical characteristics of nonradioactive gamma-LPH. However, in the conditions used, we were unable to demonstrate biosynthesis of beta-MSH. These results suggest that gamma-LPH is biosynthesized more slowly than beta-LPH and that the conversion into beta-MSH, if it exists, is a slow or subactive process in the species studied.     

Particular processing of pro-opiomelanocortin in Xenopus laevis intermediate pituitary. Sequencing of alpha- and beta-melanocyte-stimulating hormones

alpha- and beta-melanocyte-stimulating hormones (alpha-MSH and beta-MSH) have been isolated from Xenopus laevis neurointermediate pituitary and microsequenced. Intracellular alpha-MSH is not N-acetylated after proteolytic processing of pro-opiomelanocortin in contrast to mammalian alpha-MSHs. There is a high preservation of the melanotropic amino acid sequence common to all MSHs although in Xenopus beta-MSH a histidine residue replaces the glutamic acid residue found in position 8 of mammalian beta-MSHs.     

Theoretical conformational analysis of brain peptides. beta-Melanocyte-stimulating hormone

Using a semi-empirical method, an a priori conformational analysis of the octadecapeptide beta-melanocyte-stimulating hormone (beta-MSH) was carried out. The spatial structure of beta-MSH can be described by eight low-energy conformations, yielded by combinations of the most stable states of the respective free fragments. Calculations produced the values of all dihedral angles of the backbones and side chains of these forms as well as intra- and inter-residue interaction energies.     

A role for beta-melanocyte-stimulating hormone in human body-weight regulation

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.     

Alpha-melanocyte stimulating hormone increases plasma levels of glucagon and insulin in rabbits

Intravenous injections of 25 and 2.5 micrograms alpha-melanocyte stimulating hormone (alpha-MSH) increased plasma levels of glucagon, insulin and free fatty acids in fasted and fed rabbits. 45 micrograms beta-melanocyte stimulating hormone (beta-MSH) had similar effects, whereas 22 micrograms gamma-2-melanocyte stimulating hormone (gamma-MSH) was inactive. The alpha-MSH-induced increases in the plasma levels of glucagon, insulin and free fatty acids were not inhibited by alpha- or beta-adrenergic blocking drugs. The alpha-MSH-induced increases in the plasma levels of insulin were, however, augmented by phentolamine (an alpha-adrenergic receptor blocking drug). The plasma levels of glucose were increased by 25 micrograms alpha-MSH in fed rabbits, only, and were decreased by alpha-MSH during alpha-receptor blockade. The acute in vivo effects of alpha-MSH and beta-MSH on the plasma levels of glucagon, insulin and free fatty acids were rather similar to those previously reported for corticotropin (ACTH). It is possible that the 4-10 ACTH sequence, present in alpha-MSH, beta-MSH and ACTH, but not in gamma-MSH, is a message sequence for the observed effects. However, ORG 2766, a 4-9 ACTH analogue, was inactive. The mechanism by which alpha-MSH increased the plasma levels of glucagon and insulin in rabbits remains to be determined. It is possible, that the effects were mediated by both a central nervous action and a direct action on the endocrine pancreas.     

Post-translational processing of pro-opiomelanocortin (POMC)-derived peptides during fetal monkey pituitary development. II. beta-Lipotropin (beta-LPH)-related peptides

We have studied the post-translational processing of POMC-derived peptides during fetal monkey pituitary development using immunoassay and reverse-phase high-performance liquid chromatography (RP HPLC). Whole pituitary glands obtained from Day 50 and 55 fetal monkeys and separated lobes From Day 65 to 155 were extracted, fractionated, and analyzed for beta-melanotropin (beta-MSH), midportion beta-endorphin (beta-EP), and acetylated beta-EP immunoactivity. Separated adult pituitary lobes were analyzed for comparison. At Day 50, POMC-containing cells were located in both the anterior and intermediate pituitary lobes by immunofluorescence staining, the majority of these cells were localized in the anterior lobe. The Day 50 and 55 whole pituitaries contained predominantly beta-lipotropin (beta-LPH), gamma-lipotropin (gamma-LPH), beta-EP(1-31), and 2.2-kda beta-MSH. No acetylated products were found in Day 50 whole pituitary extracts. By Day 55, carboxy-shortened and acetylated beta-EPs were barely detectable in whole pituitary extracts. These forms were more apparent in the Day 65 separated neurointermediate lobe (NIL) extracts, and were similar to adult proportions by Day 80. The adult anterior lobe contained predominantly beta-LPH, beta-EP, and gamma-LPH. Adult NILs contained almost exclusively 2.2-kda beta-MSH, alpha-N-acetyl beta-EP(1-31) and alpha-N-acetyl beta-EP(1-27). The production of 2.2-kda beta-LPH in the monkey NIL indicates that monkey beta-LPH is different from rat beta-LPH in that it must contain the paired-basic cleavage site required for the formation of 2.2-kda beta-MSH that is known to be lacking in rat beta-LPH. Another finding was that monkey beta-EP contains a Tyr residue at position 27 as found in human beta-EP but appears to have the rat Gln substitution at position 31. The post-translational processing patterns characteristic of each lobe were well established by midterm fetal development (Day 80).     

Carcinoembronic antigen and endocrine response in a patient with Sipple's syndrome following surgery

Circulating carcinoembryonic antigen (CEA), calcitonin (CT) and adrenocorticotropic hormone (ACTH) and levels in tissue extracts of a patients with Sipple's syndrome were measured simultaneously. Biofocal medullary carcinoma of the thyroid gland (MCT), left adrenal phaeochromocytoma and ectopic para-aortal phaeochromocytoma had been removed in the first operation. Total thyroidectomy was performed thereafter. Evidence has been presented showing that (1) the first operation lowered the elevated serum levels of CEA and CT, and levels of CEA and CT in tissue extracts of MCT were considerably higher than those of tumor-uninvolved thyroid tissue and phaeochromocytomas; (2) markedly elevated levels of plasma ACTH were normalized by the first surgery and, in addition, immunoreactive ACTH and beta-melanocyte stimulating hormone (beta-MSH) were detected in the phaeochromocytomas removed. This is a documented case of the simultaneous production of CT and CEA by MCT associated with ectopic secretion of ACTH and beta-MSH from the phaeochromocytomas without manifesting clinical features of Cushing's syndrome and is based on the findings referred to above.     

Renal failure in otherwise uncomplicated acute viral hepatitis.

Twelve patients with otherwise uncomplicated acute viral hepatitis (two were HBsAg-positive) developed renal failure. Apart from dehydration due to repeated vomiting in one patient, no factor responsible for precipitating renal failure could be identified. The clinical course was characterised by renal failure with plasma urea concentrations reaching maximum values of 26-69 mmol/l (175-416 mg/100 ml). Ten patients needed dialysis for up to two weeks. Seven patients recovered completely, while the other five died from sepsis. The types of renal failure were similar to those described in fulminant hepatic failure and cirrhosis--namely, functional renal failure in five patients and acute tubular necrosis in seven. Two of the patients with functional renal failure later developed tubular necrosis. The mechanism responsible for renal failure in acute viral hepatitis is uncertain, though endotoxaemia may contribute.     

Identification of carp proopiomelanocortin-related peptides and their effects on phagocytes

We report the immunomodulating effects of proopiomelanocortin (POMC)-related peptides on phagocytic cells in carp. The complete amino acid sequences of two carp POMCs (I and II) were deduced from the nucleotide sequences after cDNA cloning. Both POMCs consist of 194 amino acids (91% sequence identity) including identical alpha-melanotropin (MSH) and beta-endorphin (EP). All hormonal peptides derived from two POMCs were identified by mass spectrometry after separation by high-performance liquid chromatography of an acid-acetone extract from a single pituitary. These peptides were alpha-MSH, N-Des-Ac-alpha-MSH, di-Ac-alpha-MSH, beta-MSH I, beta-MSH-II, N-Ac-beta-EP(1-29), corticotropin-like intermediate lobe peptide I and II and N-terminal peptide of POMC I and II. The immunomodulating effects of synthetic MSHs and EPs on phagocytic cells from carp head kidney were examined. Di-Ac-alpha-MSH, beta-MSH I, N-Ac-beta-EP(1-29) and beta-EP(1-29) increased the production of superoxide anion at 0.1-100 ng ml-1 for these MSHs and 1-100 ng ml-1 for EPs in RPMI 1640 medium.     

Erythropoietin therapy in patients with chronic renal failure.

Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients with varying degrees of chronic renal failure. We review these studies with particular reference to the progression of renal failure and the drug''s reported side effects. We conclude that the use of epoetin is beneficial and well tolerated and that there is no compelling evidence for the acceleration of renal failure associated with its use in patients.     

甲状腺功能减退症合并慢性肾功能衰竭5例临床分析

目的：提出一些关于早期诊治甲状腺功能减退症合并慢性肾功能不全的建议。方法：回顾性分析我科2000-2006年住院患者中甲状腺功能减退症合并肾功能衰竭病例5例,比较其临床表现和相关检查并分析其诊疗经过。结果：二种疾病不仅在其发生发展上有一定联系,而且在临床表现和相关检查上也有相似之处。二种疾病都可出现浮肿、贫血、乏力、纳差、心包积液、蛋白尿和不同程度的肾功能不全。二者合并出现时临床表现更加复杂多样,增加了临床诊断的难度。结论：在诊治此类疾病时要注意临床表现的一些细节,如心力衰竭时的相对缓脉、与肾功能不全不相适应的贫血、难治性心包积液、不明原因的肾功能损害等,以便早期正确诊治,提高诊疗水平。     

Should patients with renal failure associated with myeloma be dialysed?

In a study of renal function in multiple myeloma seven patients presented with renal failure and three developed it 16-106 months after diagnosis. All were dialysed. Infection with dehydration was a precipitating factor in all seven cases of acute or acute on chronic renal failure. Of these, two patients recovered normal renal function and one other was left with permanent renal impairment but no longer required dialysis. Results from the seven patients with acute renal failure and for the three with more chronic features support the practice of dialysis for all patients who present with renal failure. Dialysis is not indicated for those patients with progressive myelomatous disease. The study showed no evidence that chemotherapy permitted recovery from established renal failure. The prognosis in this elderly group is heavily dependent on the presence of cardiovascular or other degenerative disease.