Recent progress in hormone research最新文献

{"title":"Obesity, insulin resistance, and cardiovascular disease.","authors":"Gerald Reaven,&nbsp;Fahim Abbasi,&nbsp;Tracey McLaughlin","doi":"10.1210/rp.59.1.207","DOIUrl":"https://doi.org/10.1210/rp.59.1.207","url":null,"abstract":"<p><p>The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance - namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations -- is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"207-23"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24186674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptin signaling in the central nervous system and the periphery.","authors":"Christian Bjørbaek,&nbsp;Barbara B Kahn","doi":"10.1210/rp.59.1.305","DOIUrl":"https://doi.org/10.1210/rp.59.1.305","url":null,"abstract":"<p><p>The discovery of leptin in 1994 has led to astonishing advances in understanding the regulation of energy balance in rodents and humans. The demonstration of leptin receptors in hypothalamic regions known to play critical roles in regulating energy intake and body weight has produced considerable excitement in the field. Most attention has focused on the central actions of leptin. The receptor is present in several populations of neurons that express specific appetite-regulating neuropeptides for which both expression and release are regulated by leptin. Recent advances show that central leptin action is not limited to influencing energy balance. Leptin regulates a broad variety of processes and behaviors, such as blood pressure, neuroendocrine axes, bone mass, and immune function. The cloning of leptin receptors also led to parallel studies examining their signaling capacities in mammalian cell lines. The long-form receptor regulates multiple intracellular signaling cascades, including the classic janus activating kinase-signal transducer and activator of transcription (JAK-STAT) pathway, consistent with belonging to the cytokine-receptor superfamily and the phosphoinositol-3 kinase and adenosine monophosphate kinase pathways. Progress has been made in understanding the role of individual signaling pathways in vivo and the mechanisms by which specific neuropeptides are regulated. Regulation of the pro-opiomelanocortin (pomc) and the thyrotropin-releasing hormone (trh) genes by leptin is particularly well understood. Novel players in negative regulation of central leptin receptor signaling have been identified and open the possibility that these may be important in the development of leptin resistance and obesity. While initial focus was on the central effects of leptin, important actions have been discovered in peripheral tissues. These include roles of leptin to directly regulate immune cells, pancreatic beta cells, adipocytes, and muscle cells. Recent elucidation of a new signaling pathway in skeletal muscle affecting fatty acid metabolism has implications for regulation of insulin sensitivity and glucose metabolism. Recent progress in understanding central and peripheral leptin receptor signaling provides potential new targets for anti-obesity and anti-diabetes drug development.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"305-31"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24186679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The adrenergic pathway and heart failure.","authors":"J R Keys,&nbsp;W J Koch","doi":"10.1210/rp.59.1.13","DOIUrl":"https://doi.org/10.1210/rp.59.1.13","url":null,"abstract":"<p><p>Heart failure represents the endpoint to many triggering cardiovascular pathologies. However, there are molecular and biochemical features that remain common to the failing heart, despite the varying etiologies. Principal among these is heightened activation of the sympathetic nervous system and associated enhancement of adrenergic signaling pathways via the catecholamines, norepinephrine and epinephrine. During heart failure, several hallmark alterations in the adrenergic system contribute to loss of cardiac function. To specifically study these changes in a physiologically relevant setting, we and others have utilized advances in genetically engineered mouse technology. This chapter will discuss the many transgenic and knockout mouse models that have been developed to study the adrenergic system in the normal and failing heart. These models include genetically manipulated alterations of adrenergic receptors, linked heterotrimeric G proteins, and the regulatory G protein-coupled receptor kinases (GRKs). Among the more-interesting information gained from these models is the finding that inhibition of a particular GRK - GRK2 or beta adrenergic receptor kinase 1 (betaARK1) - is a potential novel therapeutic strategy to improve function in the setting of heart failure. Furthermore, we will discuss recent transgenic research that proposes an important role for hypertension in the development of heart failure. Overall, genetically engineered mouse models pertaining to this critical myocardial signaling system have provided novel insight into heart function under normal conditions and during states of dysfunction and failure.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"13-30"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24187853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Angiostatin and anti-angiogenic therapy in human disease.","authors":"Miriam L Wahl,&nbsp;Tammy L Moser,&nbsp;Salvatore V Pizzo","doi":"10.1210/rp.59.1.73","DOIUrl":"https://doi.org/10.1210/rp.59.1.73","url":null,"abstract":"<p><p>Many diseases have abnormal quality and/or quantity of vascularization as a characteristic feature. Cancer cells elicit the growth of new capillaries during neovascularization in a process termed angiogenesis. In diabetics, pathologic angiogenesis in various tissues is a clinical feature of many common complications. Therefore, the diabetic cancer patient warrants special consideration and extra care in the design of anti-angiogenic treatments without adverse side effects. Some treatment regimens that look promising in vitro, in animal models, or in early clinical trials may be contra-indicated for diabetics. This chapter will review the common complications of diabetes, with emphasis on the angiogenic pathology. Recent research related to the mechanism of action and basis for specificity of the anti-angiogenic peptide, angiostatin, will be the focus. The aim is to shed light on areas in which more research is needed with respect to angiostatin and other anti-angiogenic agents and the microenvironmental conditions that affect their activities, in order to develop improved therapeutic strategies for diabetic cancer patients.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"73-104"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24187856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue.","authors":"Jonathan R Seckl,&nbsp;Nik M Morton,&nbsp;Karen E Chapman,&nbsp;Brian R Walker","doi":"10.1210/rp.59.1.359","DOIUrl":"https://doi.org/10.1210/rp.59.1.359","url":null,"abstract":"<p><p>The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"359-93"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24184925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leptin receptor signaling and the regulation of mammalian physiology.","authors":"Martin G Myers","doi":"10.1210/rp.59.1.287","DOIUrl":"https://doi.org/10.1210/rp.59.1.287","url":null,"abstract":"<p><p>While the hormone leptin and its receptor were discovered relatively recently, a great deal is already known about the molecular details of leptin receptor (LR) signaling and physiologic regulation. While multiple alternatively spliced LR isoforms exist, only the long (LRb) form associates with the Janus kinase 2 (Jak2) tyrosine kinase to mediate intracellular signaling. LRb initiates signaling via three major mechanisms: 1) Tyr(985) of LRb recruits SH2-containing tyrosine phosphatase (SHP-2); 2) Tyr(1138) of LRb recruits signal transducer and activator of transcription 3 (STAT3); and 3) tyrosine phosphorylation sites on the receptor-associated Jak2 likely recruit numerous undefined signaling proteins. The Tyr(985) --> SHP-2 pathway is a major regulator of extracellular signal-regulated kinase (ERK) activation during leptin signaling in cultured cells, while the Tyr(1138) --> STAT3 pathway induces the feedback inhibitor, suppressor of cytokine signaling 3 (SOCS3), as well as important positive effectors of leptin action. The Jak2-dependent activation of the insulin receptor substrate (IRS) protein --> phosphatidylinositol 3-kinase (PI3'-K) pathway appears to regulate membrane potential in LRb-expressing neurons and contributes to the regulation of feeding. The Tyr(1138) --> STAT3 pathway mediates transcriptional regulation of the hypothalamic melanocortin pathway in vivo. This pathway is required for the regulation of appetite and energy expenditure by leptin. Interestingly, the Tyr(1138) --> STAT3 pathway does not strongly regulate neuropeptide Y (NPY) and thus is not required for the control of reproduction and growth. Thus, other as-yet-undefined leptin receptor signals are central to these and perhaps other aspects of leptin action.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"287-304"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24186678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis.","authors":"Kate L J Ellacott,&nbsp;Roger D Cone","doi":"10.1210/rp.59.1.395","DOIUrl":"https://doi.org/10.1210/rp.59.1.395","url":null,"abstract":"<p><p>The importance of the central melanocortin system in the regulation of energy balance is highlighted by studies in transgenic animals and humans with defects in this system. Mice that are engineered to be deficient for the melanocortin-4 receptor (MC4R) or pro-opiomelanocortin (POMC) and those that overexpress agouti or agouti-related protein (AgRP) all have a characteristic obese phenotype typified by hyperphagia, increased linear growth, and metabolic defects. Similar attributes are seen in humans with haploinsufficiency of the MC4R. The central melanocortin system modulates energy homeostasis through the actions of the agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), a POMC cleavage product, and the endogenous antagonist AgRP on the MC3R and MC4R. POMC is expressed at only two locations in the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) of the brainstem. This chapter will discuss these two populations of POMC neurons and their contribution to energy homeostasis. We will examine the involvement of the central melanocortin system in the incorporation of information from the adipostatic hormone leptin and acute hunger and satiety factors such as peptide YY (PYY(3-36)) and ghrelin via a neuronal network involving POMC/cocaine and amphetamine-related transcript (CART) and neuropeptide Y (NPY)/AgRP neurons. We will discuss evidence for the existence of a similar network of neurons in the NTS and propose a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH).</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"395-408"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24184926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monogenic human obesity syndromes.","authors":"I S Farooqi,&nbsp;S O'Rahilly","doi":"10.1210/rp.59.1.409","DOIUrl":"https://doi.org/10.1210/rp.59.1.409","url":null,"abstract":"<p><p>Over the past decade, we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes and the novel physiological pathways revealed by those genetic discoveries. We and others recently have identified several single-gene defects causing severe human obesity. Many of these defects have occurred in molecules identical or similar to those identified as a cause of obesity in rodents. This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"409-24"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24184927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Balancing contractility and energy production: the role of myocyte enhancer factor 2 (MEF2) in cardiac hypertrophy.","authors":"Michael P Czubryt,&nbsp;Eric N Olson","doi":"10.1210/rp.59.1.105","DOIUrl":"https://doi.org/10.1210/rp.59.1.105","url":null,"abstract":"<p><p>Cardiac hypertrophy -- that is, enlargement of the heart resulting from increased myocyte size -- is observed with many forms of human heart disease. It may arise secondary to an insult, such as infarct or chronic hypertension, or may occur as a consequence of a genetic defect, such as in hypertrophic cardiomyopathy. Traditionally, it has been widely believed that hypertrophy occurred as an adaptive response to normalize increased wall stress due to disease. Recently, however, it has been observed that while hypertrophy initially appears to improve the function of the heart following insult, over time, it frequently leads to a decompensated state, characterized by fibrosis and chamber dilation, resulting in overt heart failure. Hypertrophy also occurs during fetal development, immediately after birth, and in trained athletes; however, it does not lead to decompensation in these states. Experiments over the last 15 years have implicated similar signaling pathways in both pathological and physiological hypertrophic responses. Recently, important differences have been demonstrated that might hold the key to the development of effective new treatments for human diseases. This chapter focuses on how these hypertrophic responses differ from one another phenotypically and discusses how inefficient or impaired energy metabolism in the heart may contribute to the development of pathological responses. We also discuss recent evidence that the myocyte enhancer factor 2 (MEF2) transcription factor family, which previously has been shown to be important in cardiac development and hypertrophy, may have a role in regulation of cardiac energy metabolism.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"59 ","pages":"105-24"},"PeriodicalIF":0.0,"publicationDate":"2004-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24187857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene expression profiling for prediction of clinical characteristics of breast cancer.","authors":"Erich Huang,&nbsp;Mike West,&nbsp;Joseph R Nevins","doi":"10.1210/rp.58.1.55","DOIUrl":"https://doi.org/10.1210/rp.58.1.55","url":null,"abstract":"<p><p>We have applied techniques of gene expression analysis to the analysis of human breast cancer by identifying metagene models with the capacity to discriminate breast tumors based on estrogen receptor (ER) status as well as the propensity for lymph node metastasis. We assess the utility and validity of these models in predicting status of tumors in cross-validation determinations. The practical value of such approaches relies on the ability not only to assess relative probabilities of clinical outcomes for future samples but also to provide an honest assessment of the uncertainties associated with such predictive classifications, based on the selection of gene subsets for each validation analysis. This latter point is of critical importance to the ability of applying these methodologies to clinical assessment of tumor phenotype. It is also clear from ER predictions that these analyses identify genes known to be involved in ER function but also identify new candidate genes involved in ER function. We believe these gene expression phenotypes have the potential to characterize the complex genetic alterations that typify the neoplastic state in a way that truly reflects the complexity of the regulatory pathways that are affected.</p>","PeriodicalId":21099,"journal":{"name":"Recent progress in hormone research","volume":"58 ","pages":"55-73"},"PeriodicalIF":0.0,"publicationDate":"2003-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"22427275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}