Recent Progress In Hormone Research[JOURNAL]
Sun
200 papers
Neuroendocrinology of infection and the innate immune system.
Reichlin S
Recent Prog Horm Res · 1999 · PMID 10548875
This chapter deals with two topics: the evolutionary and functional implications of the effects of bacterial endotoxin on the neuroendocrine system in higher vertebrates and a newly recognized neuroendocrine mechanism of...
This chapter deals with two topics: the evolutionary and functional implications of the effects of bacterial endotoxin on the neuroendocrine system in higher vertebrates and a newly recognized neuroendocrine mechanism of immune regulation by the direct secretion of immunoregulatory cytokines from the brain. Endotoxin is a highly specific stimulus to hypothalamic-hypophysial activity; neuroendocrine responses are integrated with behavioral, body temperature, and innate immune responses. All depend upon the genetically programmed capacity of several classes of cells to distinguish molecular patterns foreign to self that are characteristic of pathogenic microorganisms. One component of the response to endotoxin and inflammation in the brain is the direct secretion into the blood (by bulk flow) of appreciable amounts of immunoregulatory cytokines that can modify peripheral levels of IL-6 and TNF-alpha. These can arise from activated glia, endothelia, choroid plexus, and possibly specific neuronal groups. Despite its being an "immune-privileged" organ, brain-presented antigens provoke a greater humoral immune response than by other routes. The capacities of the brain to regulate peripheral cytokine levels by their direct secretion into the blood and to induce antibody response are potential pathways of peripheral neuroimmunomodulation. This mechanism is integrated with the better-established modes of neuroimmunomodulation, sympathetic nervous system, and hypothalamic-pituitary axis.
Circadian and sleep-dependent regulation of hormone release in humans.
Czeisler CA, Klerman EB, New Collective Author
Recent Prog Horm Res · 1999 · PMID 10548874
Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiol...
Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian rhythm sleep disorders, including the dyssomnia of shift work and visual impairment. Yet to be fully investigated are the interactions of these factors with age and gender. Characterization of the factors governing hormone secretion is critical to understanding the temporal regulation of endocrine systems and presents many exciting areas for future research.
Molecular control of circadian behavioral rhythms.
Young MW
Recent Prog Horm Res · 1999 · PMID 10548873
Several genes have been recognized in Drosophila that regulate circadian rhythms. Homologues of these genes have now been found in mice and humans, suggesting a mechanism that is conserved throughout the animal kingdom....
Several genes have been recognized in Drosophila that regulate circadian rhythms. Homologues of these genes have now been found in mice and humans, suggesting a mechanism that is conserved throughout the animal kingdom. For some of these genes and their products, molecular oscillations are produced in certain cells of the Drosophila and mammalian brain. Two genes, period and timeless, are transcribed with a circadian rhythm that is regulated by activities derived from their encoded proteins, PER and TIM. Nuclear localization of these proteins downregulates per and tim transcription by suppressing the activities of two transcription factors, dCLOCK and dBMAL1. Cycles in this feedback regulation are promoted by events that regulate the accumulation, physical interaction, and nuclear translocation of PER and TIM proteins. PER and TIM must physically associate to enter the nucleus and their cytoplasmic interaction is delayed by a kinase encoded by the clock gene, double-time. This kinase directs PER phosphorylation, which leads to PER degradation. Effects of the kinase are blocked once PER is complexed to TIM. These interactions prolong the interval of per and tim transcription by ensuring that PER/TIM complexes from only after TIM has accumulated for several hours.
What makes the circadian clock tick: genes that keep time?
Sehgal A, Ousley A, Yang Z … +2 more , Chen Y, Schotland P
Recent Prog Horm Res · 1999 · PMID 10548872
Intense activity in the field of circadian rhythms has led in recent years to a basic understanding of how an endogenous clock is generated. Oscillating products of the period (per) and timeless (tim) genes, which feed b...
Intense activity in the field of circadian rhythms has led in recent years to a basic understanding of how an endogenous clock is generated. Oscillating products of the period (per) and timeless (tim) genes, which feed back to regulate their own synthesis, and transcription factors, which activate these genes, combine to generate a molecular loop that apparently drives behavioral and physiological rhythms. The best-characterized component of this system is the per gene, with considerable effort directed towards identifying the mechanisms that regulate cyclic expression of RNA and protein. Since the cycling of PER protein is controlled largely by post-transcriptional mechanisms, the relative importance of RNA versus protein cycling has been addressed in several studies that are discussed in this chapter. However, it now is clear that regulation of per cannot be dissociated from that of tim, since they are co-dependent components. The overt behavioral phenotype likely depends upon the effect that any perturbation has on both components, rather than on either alone. Major features of the feedback loop appear to be conserved, from fruit flies to mammals. One difference between the two systems is the manner in which the "molecular clock" responds to light. In flies, levels of TIM protein are reduced in response to light, while in mammals, per RNA is induced. The pathway that conducts light to the clock is poorly understood but there is increasing evidence in support of a dedicated pathway for circadian photoreception, as opposed to the sole use of the visual transduction system.
Suprachiasmatic nucleus: the brain's circadian clock.
Gillette MU, Tischkau SA
Recent Prog Horm Res · 1999 · PMID 10548871
The tiny suprachiasmatic nucleus (SCN) of the hypothalamus plays a central role in the daily programming of organismic functions by regulating day-to-day oscillations of the internal milieu and synchronizing them to the...
The tiny suprachiasmatic nucleus (SCN) of the hypothalamus plays a central role in the daily programming of organismic functions by regulating day-to-day oscillations of the internal milieu and synchronizing them to the changing cycles of day and night and of body state. This biological clock drives the daily expression of vital homeostatic functions as diverse as feeding, drinking, body temperature, and neurohormone secretion. It adaptively organizes these body functions into near-24-hour oscillations termed circadian rhythms. The SCN imposes temporal order 1) through generating output signals that relay time-of-day information, and 2) through gating its own sensitivity to incoming signals that adjust clock timing. Each of these properties, derived from the timebase of the SCN's endogenous near-24-hour pacemaker, persists when the SCN is maintained in a hypothalamic brain slice in vitro. Single-unit recording experiments demonstrate a spontaneous peak in the electrical activity of the ensemble of SCN neurons near midday. By utilizing this time of peak as a "pulse" of the clock, we have characterized a series of time domains, or windows of sensitivity, in which the SCN restricts its own sensitivity to stimuli that are capable of adjusting clock phase. Pituitary adenylyl cyclase-activating peptide (PACAP) and cAMP comprise agents that reset clock phase during the day time domain; both PACAP and membrane-permeable cAMP analogs cause phase advances only when applied during the day. In direct contrast to PACAP and cAMP, acetylcholine and cGMP analogs phase advance the clock only when applied during the night. Sensitivity to light and glutamate arises concomitant with sensitivity to acetylcholine and cGMP. Light and glutamate cause phase delays in the early night, by acting through elevation of intracellular Ca2+, mediated by activation of a neuronal ryanodine receptor. In late night, light and glutamate utilize a cGMP-mediated mechanism to induce phase advances. Finally, crepuscular domains, or dusk and dawn, are characterized by sensitivity to phase resetting by the pineal hormone, melatonin, acting through protein kinase C. Our findings indicate that the gates to both daytime and nighttime phase resetting lie beyond the level of membrane receptors; they point to critical gating within the cell, downstream from second messengers. The changing patterns of sensitivities in vitro demonstrate that the circadian clock controls multiple molecular gates at the intracellular level, to assure that they are selectively opened in a permissive fashion only at specific points in the circadian cycle. Discerning the molecular mechanisms that generate these changes is fundamental to understanding the integrative and regulatory role of the SCN in hypothalamic control of organismic rhythms.
Internet use by endocrinologists.
Blonde L, Cook JL, Dey J
Recent Prog Horm Res · 1999 · PMID 10548870
Endocrinologists, like other physicians, are information managers. They manage both disease-specific and patient-specific information and must integrate both types of information to provide the best possible care for the...
Endocrinologists, like other physicians, are information managers. They manage both disease-specific and patient-specific information and must integrate both types of information to provide the best possible care for their patients. New technologies offer abundant new approaches to medical information management tasks. Many will focus on computer hardware and software applications; others will seek solutions from video, telecommunications, the marriage of computer and consumer electronics, and other evolving technologies popularly referred to as multimedia and virtual reality. Few innovations in history have had the potential to so profoundly change our lives as the Internet. The incredible growth of the Internet to a vast system of interconnected networks serving more than 75 million users in the United States alone largely has been driven by the growth of newsgroups and e-mail, providing a means of communication among Internet users and particularly the World Wide Web (WWW). Information on web pages can be "linked" so that users can click on a link and navigate to other information on the same page, on other pages of the same document, on other files on the same computer, or on other computers linked to the Internet anywhere in the world. Moreover, the navigation requires no knowledge of arcane, difficult-to-remember commands. Hypertext links have the great utility of allowing users to navigate through information according to their own interests and information needs, as opposed to those of an author. The WWW also allows authors to link to other sources of information, rather than having to recreate it themselves. Increasingly easy access to the WWW has dramatically reduced the barriers to publication of information, since it is much easier and much less expensive to place information on the WWW than it is to publish and distribute it in hard copy form. This ease of publication has led to an incredible proliferation of information on the WWW. Much WWW information is of value to health professionals, including endocrinologists. This chapter reviews a variety of potential uses of the Internet by endocrinologists in their clinical, research, and educator roles and provides a number of examples of each. Approaches to finding useful information on the Internet are addressed. Finally, we include some speculation about the role of the Internet in the future practice of endocrinology.
Structural and molecular studies of human chorionic gonadotropin and its receptor.
Lustbader JW, Lobel L, Wu H … +1 more , Elliott MM
Recent Prog Horm Res · 1998 · PMID 9769716
Human chorionic gonadotropin (hCG) is a placental hormone that stimulates secretion of the pregnancy-sustaining steroid progesterone. It and other glycoprotein hormones are disulfide-rich heterodimers that share a common...
Human chorionic gonadotropin (hCG) is a placental hormone that stimulates secretion of the pregnancy-sustaining steroid progesterone. It and other glycoprotein hormones are disulfide-rich heterodimers that share a common alpha chain and distinctive beta chains specific to their particular G protein-linked receptors. We determined the structure of partially deglycosylated hCG at 2.6 A resolution from multiwavelength anomalous diffraction (MAD) measurements of a selenomethionyl hCG crystal. We have also begun three- and four-dimensional structural studies on the biologically active hormone and have determined the structure of the carbohydrate attached to the alpha-subunit. Despite little sequence similarity limited to 10% identity, the alpha and beta subunits of hCG maintain strikingly similar tertiary folds, with cystine-knot motifs at cores of extended hairpin loops. Structural and sequence comparisons indicate an evolutionary homology between the glycoprotein hormone chains and other cystine-knot proteins, notably PDGF, TGF-beta, and NGF. This structural similarity has led us to speculate that early hCG secretion has a broader role than solely the stimulation of the corpus luteum; indeed, levels of hCG, which rise rapidly in the circulation after implantation, are greater than the levels necessary for corpus luteum function. One such role of hCG or its subunits could be as a growth factor that facilitates endometrial receptivity. Our studies of hCG have also identified structural variants, notably in the carbohydrate moiety, that are distinctive for patients with a variety of disorders of pregnancy, including hydatidiform mole and choriocarcinoma. We have also focused our efforts on using information gleaned from the structure of hCG for the design of drug-like molecules that might serve as either agonists or antagonists of hCG. To facilitate these experiments, we have designed a rapid screen for the identification of molecules that might bind the hCG receptor by identifying compounds that disrupt binding of hCG to its receptor. This screen employs a filamentous phage that displays the extracellular domain of the hCG receptor on its surface. Thus far, we have identified a few compounds that disrupt binding of hCG with its receptor at a concentration of approximately 1 micromolar. These "lead" molecules are currently being modified in an attempt to identify a molecule that can disrupt binding of hCG at nanomolar concentrations.
Mechanisms of thyroid hormone action: insights from X-ray crystallographic and functional studies.
Ribeiro RC, Apriletti JW, Wagner RL … +9 more , West BL, Feng W, Huber R, Kushner PJ, Nilsson S, Scanlan T, Fletterick RJ, Schaufele F, Baxter JD
Recent Prog Horm Res · 1998 · PMID 9769715
This review summarizes the studies conducted in our laboratory on the mechanisms of thyroid hormone action over the past two decades. We have attempted to place our studies on thyroid hormone receptors (TRs) in perspecti...
This review summarizes the studies conducted in our laboratory on the mechanisms of thyroid hormone action over the past two decades. We have attempted to place our studies on thyroid hormone receptors (TRs) in perspective with the work conducted by other investigators that established their nuclear localization, DNA-binding properties, DNA response elements, and the role of other proteins involved in TR-mediated regulation of gene transcription. Recently, our crystallographic studies of the TR ligand binding domain (LBD) revealed that the ligand has a structural role in the folding of the receptor's hydrophobic core. The analysis of the structure led to biochemical and genetic studies that have defined the surfaces on the TR LBD required for dimerization and binding of coactivator proteins. Placement of the mutations found in patients with the syndrome of generalized resistance to thyroid hormone on the TR LBD revealed that they were restricted to amino acids in the vicinity of the binding pocket for thyroid hormone. The insights gained from the elucidation of the TR LBD structure will provide the basis for the design of compounds with selective agonistic or antagonistic activities.
Molecular cloning of (25-OH D)-1 alpha-hydroxylase: an approach to the understanding of vitamin D pseudo-deficiency.
Glorieux FH, St-Arnaud R
Recent Prog Horm Res · 1998 · PMID 9769714
Pseudovitamin D-deficiency rickets (PDDR) is the first identified inborn error of vitamin D metabolism. Its clinical course is similar to that of nutritional rickets due to simple vitamin D deficiency. The treatment of c...
Pseudovitamin D-deficiency rickets (PDDR) is the first identified inborn error of vitamin D metabolism. Its clinical course is similar to that of nutritional rickets due to simple vitamin D deficiency. The treatment of choice is replacement therapy with calcitriol [1,25(OH)2D3]. PDDR is inherited as a simple autosomal recessive trait. The PDDR locus has been mapped to chromosome 12q13-q14. The molecular defect underlying the 25-hydroxyvitamin D-1 alpha-hydroxylase enzyme dysfunction has remained elusive due to the lack of sequence information for the gene encoding the cytochrome P450 moiety of the enzyme. We have used a probe derived from the rat 25-hydroxyvitamin D-24-hydroxylase sequence to identify and clone the 1 alpha-OHase cDNA. The candidate gene was transiently expressed in P19 embryonal carcinoma cells. Only those cells that were transfected with the candidate cDNA in the sense orientation were able to produce a compound that co-eluted with the 1 alpha, 25 vitamin D3 standard. Mass spectrometry analysis confirmed the identity of the produced metabolite. A human genomic clone was isolated from a chromosome 12 cosmid library and subsequently mapped to human chromosome 12q13.1-q13.3. To address the putative biological function of 24,25-dihydroxyvitamin I) 24,25(OH)2D, we also engineered a null mutation in the 24-OHase gene in embryonic stem cells (ES). Animals heterozygous for the engineered mutation are normal and fertile. One half of the homozygous animals die before weaning. Breeding of surviving females gives an F2 generation in which bone development is abnormal at sites of intramembranous ossification. Growthplate maturation and endochondral ossification appeared to proceed normally. The results show that a complete absence of vitamin D metabolites hydroxylated in position 24 during embryogenesis leads to abnormal bone structure and suggests a key role for 24,25(OH)2D in the developmental regulation of intramembranous ossification.
Parathyroid hormone-related protein in the pancreatic islet and the cardiovascular system.
Vasavada RC, Garcia-Ocana A, Massfelder T … +2 more , Dann P, Stewart AF
Recent Prog Horm Res · 1998 · PMID 9769713
Parathyroid hormone-related protein was discovered as the causative agent responsible for the common paraneoplastic syndrome, humoral hypercalcemia of malignancy. It is now clear that the PTHrP gene is expressed in virtu...
Parathyroid hormone-related protein was discovered as the causative agent responsible for the common paraneoplastic syndrome, humoral hypercalcemia of malignancy. It is now clear that the PTHrP gene is expressed in virtually every cell and tissue in the body at some point in development or adult life and that the peptide is critical for normal life. Two of the tissues that produce PTHrP are the insulin-producing beta cells of the pancreatic islet and the vascular smooth muscle cells of the arterial wall. In this review, the physiologic roles of PTHrP in the islet and in the arterial wall are explored. PTHrP is a classical neuroendocrine prohormone that undergoes extensive post-translational processing to yield a family of daughter peptides that are the mature secretory forms of the peptide. In addition to its ability to act as a traditional endocrine, paracrine, or autocrine factor, PTHrP appears to be able to act as an "intracrine" factor as well, directly entering the nucleus after translation and stimulating proliferation, apoptosis, and perhaps other cellular responses as well. The cell biology underlying this phenomenon is also explored herein.
Functional analysis of the PTH/PTHrP network of ligands and receptors.
Kronenberg HM, Lanske B, Kovacs CS … +5 more , Chung UI, Lee K, Segre GV, Schipani E, Jüppner H
Recent Prog Horm Res · 1998 · PMID 9769712
Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are two related proteins that activate a common PTH/PTHrP receptor, yet have quite distinct physiologic missions. PTH is the major peptide regulat...
Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) are two related proteins that activate a common PTH/PTHrP receptor, yet have quite distinct physiologic missions. PTH is the major peptide regulator of blood calcium in higher vertebrates, while PTHrP predominantly acts as a paracrine regulator of differentiation and local intercellular signaling. To analyze the physiological roles of PTHrP and the PTH/PTHrP receptor, "knockout" mice missing either the PTHrP or the PTH/PTHrP receptor gene were developed. Both the PTHrP (-/-) mice and the PTH/PTHrP receptor (-/-) mice exhibit a growth plate chondrodysplasia that reflects accelerated differentiation of proliferating chondrocytes. Growth plate chondrocytes regulate the local production of PTHrP by secreting the protein, Indian hedgehog (Ihh), as they are leaving the proliferative pool. Ihh stimulates the production of PTHrP, which then slows the differentiation of chondrocytes, thereby delaying the production of Ihh. PTHrP also stimulates transport of calcium across the placenta. PTHrP (-/-) mice lack the normal elevation of fetal blood calcium (when compared to maternal levels) and have low placental transport of calcium. Fragments of PTHrP that do not bind to the PTH/PTHrP receptor can correct the defect of placental calcium transport in these mice. Thus, this action of PTHrP is not mediated by the PTH/PTHrP receptor. The "knockout" mice thus help delineate the roles of PTH. PTHrP, and the PTH/PTHrP receptor in an interacting network of ligands and receptors.
The calcium-sensing receptor (CaR) permits Ca2+ to function as a versatile extracellular first messenger.
Brown EM, Chattopadhyay N, Vassilev PM … +1 more , Hebert SC
Recent Prog Horm Res · 1998 · PMID 9769711
The ability of parathyroid cells to recognize and respond to (i.e., "sense") small changes in the extracellular Ca2+ concentration (Ca2+o) plays a crucial role in mineral ion homeostasis. Expression cloning in Xenopus la...
The ability of parathyroid cells to recognize and respond to (i.e., "sense") small changes in the extracellular Ca2+ concentration (Ca2+o) plays a crucial role in mineral ion homeostasis. Expression cloning in Xenopus laevis oocytes enabled isolation of a cDNA coding for the bovine parathyroid CaR. CaRs were later isolated from human parathyroid and kidney, rat kidney, brain and C-cell, rabbit kidney, and chicken parathyroid. All are tissue and species homologs of the same ancestral gene. The predicted CaR protein has a large extracellular amino-terminus, which binds polycationic CaR agonists; a central core with seven membrane-spanning helices, documenting that it is a G protein-coupled receptor; and an approximately 200 amino acid carboxyl-terminal tail. The CaR is highly expressed in parathyroid and C-cells, along almost the entire nephron and gastrointestinal (GI) tract and within numerous regions of the brain, particularly hippocampus, cerebellum, and hypothalamus. The CaR's physiological importance has been documented by the identification of hyper- and hypocalcemic syndromes due to inactivating or activating CaR mutations, respectively. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are caused by loss-of-function CaR mutations producing Ca2+o "resistance," while autosomal dominant hypocalcemia is the result of activating mutations rendering CaRs overly sensitive to Ca2+o. In addition to showing altered parathyroid responsiveness to Ca2+o, patients with FHH reabsorb too much urinary Ca2+ and Mg2+ at a given Ca2+o, while those with autosomal dominant hypocalcemia excrete too much, illustrating the CaR's key role in renal handling of divalent cations. Recent in vitro data suggest that the CaR directly regulates renal water handling in the collecting duct. Indeed, patients with FHH concentrate their urine normally, despite their hypercalcemia, while those with autosomal dominant hypocalcemia can exhibit impaired urinary concentration at normal or even low Ca2+o, suggesting that the CaR enables coordination of renal calcium and water handling. In addition to serving these "homeostatic" roles, the CaR likely also enables Ca2+o to serve additional roles as an extracellular messenger. The receptor regulates key Ca2+ and K(+)-permeable ion channels in hippocampal and other brain cells and likely senses local changes in Ca2+o within the brain microenvironment accompanying neuronal activation. It is also present in and regulates ion channels in lens epithelial cells, potentially playing some role in cataract development in hypoparathyroid patients. In keratinocytes and epithelial cells of the gastrointestinal tract, in contrast, the CaR may regulate cellular proliferation and differentiation, processes known to be modulated by Ca2+o in these cell types. Thus, in addition to sensing and regulating systemic Ca2+o, the CaR likely enables Ca2+o to act as a local signal for cells within specific microenvironments, such as the brain or eye.
Phenotype and genotype in polycystic ovary syndrome.
Legro RS, Spielman R, Urbanek M … +3 more , Driscoll D, Strauss JF, Dunaif A
Recent Prog Horm Res · 1998 · PMID 9769710
Polycystic ovary syndrome (PCOS) is a common disorder in premenopausal women and is characterized by hyperandrogenic chronic anovulation. The cause is unknown. PCOS is associated with significant insulin resistance as we...
Polycystic ovary syndrome (PCOS) is a common disorder in premenopausal women and is characterized by hyperandrogenic chronic anovulation. The cause is unknown. PCOS is associated with significant insulin resistance as well as with defects in insulin secretion. These abnormalities place these women at substantial risk for developing type 2 diabetes mellitus. A defect in insulin-mediated receptor autophosphorylation has been found in a substantial proportion of PCOS women. Both PCOS and the insulin resistance that accompanies it appear to have major genetic components. Family studies of PCOS have supported this, although they suffer from incomplete phenotyping of probands and first-degree relatives. The phenotype in males and nonreproductive age females is uncertain. Despite the shortcomings of the family studies of PCOS, they have consistently indicated familial clustering and suggested that the mode of inheritance is dominant. Our initial studies of 50 families of PCOS probands indicate that 24% of sisters are affected with PCOS. There also appears to be an intermediate phenotype of sisters with regular menstrual cycles who are hyperandrogenic per se (22% of sisters). Additionally, there appears to be a major familial defect, with 50% of first-degree relatives having glucose intolerance (impaired glucose tolerance by oral glucose tolerance test or type 2 diabetes mellitus). These findings suggest that hyperandrogenism in females and glucose intolerance may be genetic traits in PCOS kindreds. Systematic phenotyping will allow assignment of affected status for eventual linkage analysis.
Genetics of type II diabetes.
Permutt MA, Chiu K, Ferrer J … +5 more , Glaser B, Inoue H, Nestorowicz A, Stanley CA, Tanizawa Y
Recent Prog Horm Res · 1998 · PMID 9769709
Defining the genetic basis of Type II or non-insulin dependent diabetes mellitus (NIDDM) will accelerate our progress toward understanding its etiology and will provide new therapeutic targets for treatment of this commo...
Defining the genetic basis of Type II or non-insulin dependent diabetes mellitus (NIDDM) will accelerate our progress toward understanding its etiology and will provide new therapeutic targets for treatment of this common disease. Here we present a brief overview of the history of the search for diabetes genes and report current strategies employed by our laboratory and by others in this effort. Isolation and subsequent mapping of candidate genes involved in insulin production and action has been a major effort in this field. Our lab has focused on pancreatic islet beta-cell genes, since the insulin lack of NIDDM is often the result of resistance to the action of insulin that is superimposed on a limited ability to produce insulin. A number of islet genes have been evaluated, including those involved in glucose metabolism, islet K+ channel genes, and transcription factors. For each gene, human cDNAs and genomic clones have been isolated and simple sequence repeat polymorphisms (SSRPs) identified. The SSRPs were used to map the genes by linkage in CEPH pedigrees, or sequence-tagged sites (STSs) were used to map the genes to radiation hybrids (RH) or to YAC clones containing SSRPs. The SSRPs have then been used as markers for linkage analyses in families with NIDDM. Mutation screening by single-strand conformational polymorphism analysis and by sequencing has revealed variants that have been tested in association studies. A strategy was devised to generate novel expressed sequence tags (ESTs) from human pancreatic islet genes by differential display of islet mRNA. In the first phase of this project we identified 42 cDNAs that were preferentially expressed in pancreatic islets relative to exocrine tissue. When compared to sequences in GenBank, novel genes were represented by 69%. Enhanced islet expression was confirmed by Northern analysis of RNA. Sequence-tagged sites were synthesized for a number of islet ESTs and used to map these genes to human chromosomes. This strategy provides an effective means to selectively identify and map genes transcribed in human pancreatic islets and to identify novel islet candidate genes for NIDDM. Positional cloning of NIDDM genes in families of various racial groups is being conducted by a number of labs. Although regions of genetic susceptibility are being identified, finding the genes within these regions will be difficult because of the polygenic nature of the disease As an alternative strategy, we have begun to map genes responsible for monogenic disorders of carbohydrate metabolism. Familial hyperinsulinism (HI, OMIM #256450) is a rare recessive disease associated with neonatal hyperinsulinism and life-threatening hypoglycemia. To determine the molecular basis for HI, we mapped the gene in multiplex families to chromosome 11p14-15.1. A candidate gene, the sulfonylurea receptor (SUR1), was mapped to the region and shown to harbor mutations in HI patients. Analysis of 21 identified mutations has revealed the role of SUR1 as a nucleotide regulator of the islet ATP-sensitive K+ channel. The challenge for the future will be to utilize the information provided by the Human Genome Project (i.e., the complete nucleotide sequence and expression maps of the genome) to find diabetes-predisposing genes. Our immediate goals include collecting families with NIDDM for phenotyping and for DNA analysis and continuing to identify suitable candidate genes to be studied in these families.
Life without neuropeptide Y.
Palmiter RD, Erickson JC, Hollopeter G … +2 more , Baraban SC, Schwartz MW
Recent Prog Horm Res · 1998 · PMID 9769708
Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to...
Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
Cyclic AMP, PKA, and the physiological regulation of adiposity.
McKnight GS, Cummings DE, Amieux PS … +5 more , Sikorski MA, Brandon EP, Planas JV, Motamed K, Idzerda RL
Recent Prog Horm Res · 1998 · PMID 9769707
The major regulator of lipolysis in white adipocytes and brown adipocytes is cAMP and the actions of cAMP are mediated by protein kinase A (PKA). Multiple subunits of PKA, including RII beta, R1 alpha, C alpha, and C bet...
The major regulator of lipolysis in white adipocytes and brown adipocytes is cAMP and the actions of cAMP are mediated by protein kinase A (PKA). Multiple subunits of PKA, including RII beta, R1 alpha, C alpha, and C beta 1, are expressed in fat cells but the major holoenzyme assembled under normal conditions contains RII beta and C alpha. Targeted disruption of the RII beta gene in mice revealed that both white and brown adipocytes are capable of compensating by increasing the level of RI alpha. Nevertheless, the mice display a lean phenotype, have an elevated metabolic rate due to activation and induction of uncoupling protein in brown fat, and are resistant to diet-induced obesity and insulin resistance. Although the metabolic disturbances in white and brown fat tissue may explain most of the phenotypic changes, the loss of neuronal expression of RII beta may also contribute to the alterations in energy balance. Specific neuronal defects have been characterized that prevent the normal changes in gene expression seen with drugs that act through the dopaminergic pathway. The RII beta mutant mouse provides an interesting model of obesity resistance and demonstrates that chronic changes in the PKA signaling system can lead to stable alterations in energy storage and utilization.
The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action.
White MF
Recent Prog Horm Res · 1998 · PMID 9769706
Abstract loading — click title to view on PubMed.
The MONA LISA hypothesis in the time of leptin.
Bray GA, York DA
Recent Prog Horm Res · 1998 · PMID 9769705
The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a cont...
The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.
Signaling in and regulation of ionizing radiation-induced apoptosis in endothelial cells.
Billis W, Fuks Z, Kolesnick R
Recent Prog Horm Res · 1998 · PMID 9769704
Exposure of mammalian cells to ionizing radiation leads primarily to DNA damage-induced cell death. The induction of apoptosis by ionizing radiation represents an alternative mode to cell kill. Breakdown of sphingomyelin...
Exposure of mammalian cells to ionizing radiation leads primarily to DNA damage-induced cell death. The induction of apoptosis by ionizing radiation represents an alternative mode to cell kill. Breakdown of sphingomyelin to produce ceramide by activation of sphingomyelinase is one of the upstream signalling cascades activated in apoptotic cells in response to stimuli such as TNF. Using genetic models of acid sphingomyelinase deficiency, the ceramide generated by radiation-induced activation of sphingomyelinase has been shown to serve as a second messenger in initiating an apoptotic response. PKC activation represents an upstream anti-apoptotic checkpoint at the sphingomyelinase level as well as a checkpoint downstream of ceramide generation. The balance between these pro- and anti-apoptotic systems may determine the magnitude of the observed apoptotic response.
Signaling via JAK tyrosine kinases: growth hormone receptor as a model system.
Carter-Su C, Smit LS
Recent Prog Horm Res · 1998 · PMID 9769703
During the past 4 years, significant progress has been made in elucidating the earliest events following binding of ligands to members of the cytokine receptor superfamily. This is a rapidly growing family of receptors t...
During the past 4 years, significant progress has been made in elucidating the earliest events following binding of ligands to members of the cytokine receptor superfamily. This is a rapidly growing family of receptors that currently includes receptors for growth hormone (GH); prolactin; erythropoeitin; granulocyte colony-stimulating factor; granulocyte macrophage colony-stimulating factor; interleukin(IL)s 2-7, 9-13, 15; interferon (IFN)-alpha, beta, and gamma; thrombopoietin; leptin; oncostatin M; leukemia inhibitory factor (LIF); ciliary neurotrophic factor; and cardiotropin-1. Despite their diverse physiological effects in the body, ligands that bind to members of this family share multiple signaling pathways. An early and most likely initiating event for all of them is the activation of one or more members of the Janus (or JAK) family of tyrosine kinases. The activated JAK kinases, which form a complex with the cytokine receptor subunits, phosphorylate themselves as well as the receptor. These phosphorylated tyrosines form binding sites for various signaling molecules that are themselves thought to be phosphorylated by JAK kinases, including 1) signal transducers and activators of transcription (Stats), which regulate transcription; 2) She proteins that recruit Grb2-SOS complexes, thereby initiating the Ras-MAP kinase pathway; and 3) insulin receptor substrate (IRS) proteins that are thought to regulate metabolic events in the cell. Additional other signaling molecules have been implicated in signaling by some cytokines, including protein kinase C, SH2-B beta, and intracellular Ca. This review uses the GH receptor as a model system for studying cytokine signaling and summarizes some of the data used to establish JAK2 as a GH receptor-associated tyrosine kinase and to identify signaling molecules that lie downstream of JAK2. Since these pathways are shared by multiple cytokines, this review also discusses factors that might contribute to specificity of response to different cytokines.
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