The role of lipotropins as hematopoietic factors and their potential therapeutic use.

Lipotropins are peptides that act as hormones that are released from a common precursor together with other physiologically important peptides; their function is to mobilize the lipids that are stored in adipocytes as an energy reserve. This review will explain the existing scientific evidence on the action of lipotropins in adipocytes and, specifically, when these lipotropins activate bone marrow adipocytes to function as hematopoietic factors and suggest the potential therapeutic use of lipotropins based on these effects.

[Protein hormones, receptors, and other proteins in mechanisms of hormonal regulation]. / Belkovye gormony, retseptory i drugie belki v mekhanizmakh gormonal'noi reguliatsii.

The amino acid sequence of porcine beta-lipotropin was the first protein primary structure studied in Russia. This peptide as well as ACTH is liberated after proteolysis of proopiomelanocortin (POMC). alpha-MSH and beta-MSH (melanocortins), which are the fragments of ACTH and beta-lipotropin respectively, are the mediators of leptin action on appetite and lipid metabolism. The structure and molecular aspects of hormone signaling of the membrane receptors of leptin and melanocortins were analysed in the connection to the regulation of food consumption, growth, and puberty. Some aspects of insulin receptor and IGF-I receptor as well as intracellular receptors of lipid hormones (steroid and thyroid hormones) were also discussed. The postulate: "All organs, tissues, and cells of humans and animals are endocrine" is formulated on the basis of the accumulated data.

Quantitative peptidomics of pituitary glands from mice deficient in copper transport.

We previously described a method of quantitating levels of peptides in Cpe(fat)/Cpe(fat) mice using affinity chromatography to isolate peptide-processing intermediates and differential isotopic labeling/mass spectrometry. In the present study, we compared two different isotopic labels, acetic anhydride and succinic anhydride for detection and quantitation of peptides in wild type mice. As previously found for acetic anhydride, succinic anhydride efficiently labels all primary amines in various peptides. Of these two reagents, succinic anhydride provides better resolution between the heavy and light peaks of the labelled peptides due to a greater mass difference between the deuterated (heavy) and non-deuterated (light) form of this label (4 Da for succinate, 3 Da for acetate). Using succinic anhydride labeling, the accuracy of measuring 1:1 and 1:2 ratios of peptides in pituitary extracts was within 5% of the theoretical value for most peptides. The accuracy with succinic anhydride is comparable to the accuracy of acetic anhydride and more peptides could be detected and quantitated with succinic anhydride. The two labels were then used to examine pituitary peptides in mice with a defect in copper transport (Atp7a mice) vs wild type mice. Using succinic anhydride, 13 peptides could be detected, 12 of which matched the theoretical mass of known pituitary peptides. Five of the six peptides which contain C-terminal amide groups were significantly decreased in the Atp7a mice relative to wild type mice, whereas only one non-amidated peptide was significantly decreased in Atp7a mice. With acetic anhydride, only five peptides could be quantitated. The three peptides which contain C-terminal amide groups were decreased approximately 30% in the Atp7a mice. The selective decrease in amidated peptides in Atp7a mice is consistent with the copper-requirement of the enzyme that forms C-terminal amides.

POMC-derived peptides and their biological action.

It has long been known that a large number of POMC-related peptides are found in skin. In this introduction I describe the formation of POMC-derived peptides in various tissues to indicate that processing is largely tissue-dependent. I focus on the peptides from the N-terminal fragment, such as gamma-MSH, ACTH and alpha-MSH, and beta-lipopropin as well as beta-endorphin. I touch on the factors that control the synthesis of the various peptides, which are now numerous and varied, and again are tissue specific. The biologic activity of the peptides generated from POMC are described in relation to their possible action in skin. In addition, I describe a new class of peptides induced in skin following injury and which are of great interest.

[Beta-lipotropin and beta-endorphin in the hypothalamic syndrome]. / Beta-lipotropin i beta-éndorfin pri gipotalamicheskom sindrome.

Experiments were conducted on 90 non-strain male albino rats to study the possibility of compensating food intake and the functions related to its activity in disturbances caused by damage to the arcuate region of the hypothalamus. Neuropeptides beta-lipotropin (beta-LTP) and beta-endorphin were chosen as the compensation factors. The registered parameters were as follows: the volume of food and water intake, feeding and drinking behaviors, orientating-exploratory activity, comforting behavior, and the duration of sleep and drowsiness. It was established that destruction of the hypothalamic arcuate zone is attended by the formation of a specific syndrome including disorders of food and water intake and other forms of behavior. Intraventricular injections of beta-LPT and beta-endorphin under such conditions was conductive to the restoration of the disturbed functions and compensated for food intake and other related functions.

Immunohistochemical study on the development of the adenohypophysial cells in the lizard Gallotia galloti.

Immunohistochemical methods have been used to study the embryonic and postnatal development of the hormone-producing cells in the adenohypophysis of the lizard Gallotia galloti. In this species, Rathke's pouch is formed between stages 30 to 32 of the embryonic development, although the first sign of immunoreactivity to antisera against adenohypophysial hormones occurs in stage 33 in the pars distalis anlage. These cells derive from the dorsal face of Rathke's pouch and are immunoreactive to anti-ACTH serum. The cytodifferentiation of ACTH and MSH cells occurs in the pars intermedia in stage 34. The TSH cells appear at stage 35 and the gonadotrope cells at stage 37. These cells derive from both the dorsal and ventral face of the Rathke's pouch. The LTH cells are revealed at stage 39 and are only originated from the dorsal face. The STH cells, which come from the dorsal as well as ventral face, are the last secretory cells differentiated just before hatching. During postnatal development an increase and also a redistribution of the immunoreactive cells occur until acquiring the adult distribution.

Evidence for a role of endorphins in the cardiovascular pathophysiology of primate shock.

Using the opiate receptor antagonist naloxone, we tested the hypothesis that endorphins act on opiate receptors to cause cardiovascular depression in primate shock. Mean arterial pressure (MAP), cardiac output, and left ventricular contractility (LV dP/dtmax) were measured in 34 anesthetized cynomolgus monkeys. Hemorrhagic shock was induced by bleeding into a heparinized reservoir to achieve (t = 0) and maintain MAP at 45 mm Hg. At t = 60 min, the reservoir was clamped and the animals were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 5) or 0.9% NaCl as a control (n = 5). There were no significant differences in the cardiovascular responses to naloxone and saline when acid-base balance and core body temperature were not controlled. Pressor responses to naloxone, however, were present in proportion to arterial pH and body temperature. When these factors were controlled, naloxone (n = 6) significantly increased MAP and LV dP/dtmax by 48% and 83%, respectively, whereas saline (n = 6) had no significant effect. Blood was reinfused at t = 120 min, and survival rate at 72 h was significantly (p = .01) higher with naloxone (3/6) than saline controls (0/6). In the endotoxic shock model, cynomolgus monkeys were treated with 2 mg/kg plus 2 mg/kg.h naloxone (n = 6) or 0.9% NaCl (n = 6) when MAP reached 75 mm Hg or its nadir 60 to 90 min after Escherichia coli endotoxin, 5 mg/kg iv. Naloxone significantly increased MAP and LV dP/dtmax by 24% and 22%, respectively, whereas saline had no effect. Survival rate at 48 h was significantly (p = .01) higher with naloxone (6/6) than saline (1/6). Plasma beta-endorphin and beta-lipotropin concentrations rose three to five-fold in both shock models and were not affected by treatment. We conclude that endorphins are activated in primate shock and act on opiate receptors to contribute to the cardiovascular depression found with hemorrhage and endotoxemia.

[The role of "beta-endorphin & beta-lipotropin" on the gonadotropin regulation in the mechanism of human ovulation].

The aim of this study is to elucidate the role of "beta-endorphin (beta-End) & beta-lipotropin (beta-LPH)" on the regulation of gonadotropin (Gn) secretion. We investigated the relationships between immunoreactive beta-End plus beta-LPH and Gn in peripheral plasma of normal menstruating women, 1) during periovulatory period, especially at the time of Gn surge, 2) at the estrogen induced Gn surge (positive feedback) and 3) at the time of hypoxic stress. Plasma concentrations of beta-End plus beta-LPH were measured as immunoreactive beta-End (i-beta-End) by RIA after extraction with Sep-Pak C18. First, we assessed pulsatile Gn secretions during periovulatory period in 19 normal women every 10 minutes for 4 hours, some women were at the time of Gn surge in its ascending limb, plateau of the peak, and descending limb of the surge. Meanwhile, circadian variations of plasma i-beta-End levels of these subjects were assessed at 4 hours' interval on the same day. In two subjects, on the day before the onset of LH surge, significantly low (p less than 0.05) basal and peak levels of i-beta-End were observed, although the basic patterns of circadian rhythm were preserved. Secondly, changes of plasma i-beta-End levels during estrogen (estradiol benzoate 1mg i.m.) induced positive feedback tests were evaluated in 16 normal women and 6 hypothalamic amenorrheic women by daily blood sampling. In normal subjects, small but significant increases (p less than 0.05) of plasma i-beta-End were observed when Gn showed initial decreases at 48 hours after injection. Subsequently at 72 hours, however, plasma i-beta-End decreased precipitously at the time of Gn surge. On the other hand, in hypothalamic amenorrheic women who were devoid of Gn surge, no significant changes of plasma i-beta-End levels were observed. The transient decreases of plasma i-beta-End just prior to the Gn surge support the idea that i-beta-End exerts tonic inhibition on the onset of Gn surge and the disappearance of its inhibition might trigger the positive Gn surge. And it was also suggested that release mechanisms of both i-beta-End and Gn are impaired in hypothalamic amenorrhea. Thirdly, in acute hypoxic stress experiment, 5 normal female volunteers were placed in hypobaric (500 mbar) condition in which oxygen supply is a half of atmosphere, simultaneous blood samplings of Gn, prolactin and i-beta-End were performed every 15 minutes for 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of cholecystokinin and opioid peptides in control of food intake.

Of the many factors that influence food intake, there is strong evidence that opioid and CCK peptides, which stimulate feeding and elicit satiety, respectively, are important components that may act in concert to regulate energy balance. Cholecystokinin peptides have been isolated in both the brain and gastrointestinal tract, and changes in concentration in the brain and in plasma have been shown to vary with feeding. Peripherally injected CCK has been shown to elicit satiety in many species, including humans, an effect that may be mediated in the CNS via the vagus. In several species, most notably the sheep, direct injection into the CSF potently decreases food intake. Questions remaining regarding the role of CCK peptides in eliciting satiety include the sites and mechanisms of action. It is unknown whether CCK acts directly on receptors, indirectly on some other parameter, or as a neurotransmitter. Although opioid peptides have also been localized in portions of both the periphery and brain, a specific physiological role for their presence has not yet been determined. Opioid peptides from three families--endorphins, enkephalins, and dynorphins--have been shown to stimulate feeding in various species. They have been active at several opioid receptor types in the CNS, but there is limited evidence to suggest they affect food intake when administered peripherally. In contrast, peripheral injection of opiate antagonists has effectively decreased food intake, an observation that led to the original hypothesis that opioids were involved in the hunger component in the control of food intake and that excess concentrations might be involved in the development of obesity. An increasing body of evidence supports the concept that opioid and CCK peptides may interact to control food intake, but the evidence is more suggestive than conclusive.

Laboratory diagnosis of hypopituitarism.

Hypopituitarism can be caused by failure or loss of one or more of the eight identifiable hormones in the anterior lobe of the pituitary gland. The endocrine manifestations of hypopituitarism are related to the type and degree of hormonal deficiency and the stage in life during which the deficiency occurs. In patients with suspected hypopituitarism, the diagnostic approach consists of determining the extent and the cause of the hormonal loss. Specific provocative tests for the diagnosis of hypopituitarism are reviewed in detail in this article.

Physiologic concentrations of beta-lipotropin stimulate lipolysis in rabbit adipocytes.

The proopiocorticomelanotropin (POMC) sequence beta-lipotropin stimulates glycerol release from incubated rabbit adipocytes at a minimal concentration of 10(-9) mol/L. However, when lipolysis inhibiting substances (eg, fatty acids and adenosine) and contaminating peptide degrading activity are continuously removed by fat cell perifusion, the sensitivity is increased to 10(-13) and partly to 10(-14) mol/L beta-lipotropin. This higher sensitivity of the perifused adipocyte could also be demonstrated with alpha-MSH (from 5 X 10(-10) to 10(-13) mol/L). The restimulation of glycerol release was shown for both peptides. We conclude that POMC peptides might be involved in the regulation of lipolysis since the minimal effective concentrations are near to plasma concentrations.

Endorphins and exercise in females: possible connection with reproductive dysfunction.

Currently available measurements of beta-endorphin and beta-lipotropin in exercising women are in excellent agreement and indicate a 2-3 fold increase over basal levels. Possible effects of exercise upon the transfer of endorphins from the peripheral circulation to the brain are examined, and evidence is presented that suggests the occurrence of a concomitant exercise-related increase of endorphins in both humoral and central nervous system compartments. Steady-state measurements of circulating luteinizing hormone and follicle-stimulating hormone levels in oligo-amenorrheic athletes, on the other hand, do not agree. It is felt that the lack of consensus may be attributable partly to technical inadequacies and partly to lack of awareness of the need for frequent sampling. The bulk of the findings suggest a tendency for luteinizing hormone levels to be low and follicle-stimulating hormone levels to be normal or low, a pattern compatible with repeated activation of the CRH-ACTH-POMC system as a result of exercise.

Exercise and endorphins--male responses.

The discovery of the endogenous opiates in the mid-1970's has led to a tremendous scientific effort attempting to determine the physiological role of these peptides. An increase in the peripheral plasma levels of beta-endorphin in humans after exercise has been noted by all investigators to date. This indication that the endogenous opiate system is activated during exercise should stimulate investigators to use exercise and training as models to aid in the understanding of these peptides. Unlike most other endocrines, plasma levels of beta-endorphin do not increase proportionally to work intensity. This conclusion is based on only one study and requires corroboration. All human studies to date have used radioimmunoassays, with one exception, and interestingly that study showed no consistent change in plasma levels of leucine enkephalin-like radioreceptor assayable ligands. In males, essentially no information is available concerning the effects of training on either acute or chronic responses to exercise. Studies using opiate antagonists (receptor type-specific) in human and animal models should prove useful in establishing or disproving roles for these peptides in appetite, pain perception, temperature regulation, metabolism, ventilation, and blood pressure control during exercise.

Affective beneficence of vigorous physical activity.

Vigorous exercise is associated with a sensation of well-being, and this subjective state has been objectively quantified with psychometric, cardiovascular, and neurophysiological data. Reductions in state anxiety have been demonstrated to follow acute physical activity, and this response persists for 2-5 h. Chronic physical activity has been associated with reductions in anxiety and depression, as well as increases in self-esteem. This research has been limited to designs of a correlational nature, and the issue of causality vs mere association has not been resolved or addressed. Three hypotheses based upon distraction, monoamine metabolism, and endorphin release are discussed in this paper. Investigators have traditionally attempted to illustrate the mechanism involved in improved mood following exercise by testing one of these or related hypotheses, but it is likely that advances will not be made in this area until these hypotheses are examined in a multiple or synergistic manner. It is concluded that each of the hypotheses reviewed remains tenable.