Showing papers in "Hormone Molecular Biology and Clinical Investigation in 2014"
TL;DR: It appears that interactions between angiotensin II and leptin/adiponectin imbalance may be important mediators of the elevated risk of developing type 2 diabetes mellitus and cardiovascular diseases associated with abdominal obesity.
Abstract: The metabolic syndrome comprises a cluster of cardiometabolic risk factors, with insulin resistance and adiposity as its central features. Identifying individuals with metabolic syndrome is important due to its association with an increased risk of coronary heart disease and type 2 diabetes mellitus. Attention has focused on the visceral adipose tissue production of cytokines (adipokines) in metabolic syndrome and type 2 diabetes mellitus, as the levels of the anti-inflammatory adipokine adiponectin are decreased, while proinflammatory cytokines are elevated, creating a proinflammatory state associated with insulin resistance and endothelial dysfunction. In this review, we will give special attention to the role of the leptin/adiponectin ratio. We have previously demonstrated that in individuals with severe coronary artery disease, abdominal obesity was uniquely related to decreased plasma concentrations of adiponectin and increased leptin levels. Leptin/adiponectin imbalance was associated with increased waist circumference and a decreased vascular response to acetylcholine and increased vasoconstriction due to angiotensin II. Leptin and adiponectin have opposite effects on subclinical inflammation and insulin resistance. Leptin upregulates proinflammatory cytokines such as tumor necrosis factor-α and interleukin-6; these are associated with insulin resistance and type 2 diabetes mellitus. In contrast, adiponectin has anti-inflammatory properties and downregulates the expression and release of a number of proinflammatory immune mediators. Therefore, it appears that interactions between angiotensin II and leptin/adiponectin imbalance may be important mediators of the elevated risk of developing type 2 diabetes mellitus and cardiovascular diseases associated with abdominal obesity.
291 citations
TL;DR: Preclinical observations have gained additional significance with the recent discovery that active BAT is present in adult humans and can be detected by 18fluor-deoxy-glucose positron emission tomography coupled with computed tomography.
Abstract: The growing understanding of adipose tissue as an important endocrine organ with multiple metabolic functions has directed the attention to the (patho)physiology of distinct fat depots. Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). This process is mediated by the major thermogenic factor uncoupling protein-1 and can be activated by certain stimuli, such as cold exposure, adrenergic compounds or genetic alterations. White adipose tissue (WAT) depots, however, also possess the capacity to acquire brown fat characteristics in response to thermogenic stimuli. The induction of a BAT-like cellular and molecular program in WAT has recently been termed "browning" or "beiging". Promotion of BAT activity or the browning of WAT is associated with in vivo cold tolerance, increased energy expenditure, and protection against obesity and type 2 diabetes. These preclinical observations have gained additional significance with the recent discovery that active BAT is present in adult humans and can be detected by 18fluor-deoxy-glucose positron emission tomography coupled with computed tomography. As in rodents, human BAT can be activated by cold exposure and is associated with increased energy turnover and lower body fat mass. Despite the tremendous progress in brown fat research in recent years, pharmacological concepts to harness BAT function therapeutically are currently still lacking.
149 citations
TL;DR: The characterization of the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.
Abstract: Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.
134 citations
TL;DR: This review focuses on the deleterious mechanisms postulated to drive the differential metabolic response between central and lower body adipose tissue distribution.
Abstract: Obesity is linked to numerous comorbidities that include, but are not limited to, glucose intolerance, insulin resistance, dyslipidemia, and cardiovascular disease. Current evidence suggests, however, obesity itself is not an exclusive predictor of metabolic dysregulation but rather adipose tissue distribution. Obesity-related adverse health consequences occur predominately in individuals with upper body fat accumulation, the detrimental distribution, commonly associated with visceral obesity. Increased lower body subcutaneous adipose tissue, however, is associated with a reduced risk of obesity-induced metabolic dysregulation and even enhanced insulin sensitivity, thus, storage in this region is considered protective. The proposed mechanisms that causally relate the differential outcomes of adipose tissue distribution are often attributed to location and/or adipocyte regulation. Visceral adipose tissue effluent to the portal vein drains into the liver where hepatocytes are directly exposed to its metabolites and secretory products, whereas the subcutaneous adipose tissue drains systemically. Adipose depots are also inherently different in numerous ways such as adipokine release, immunity response and regulation, lipid turnover, rate of cell growth and death, and response to stress and sex hormones. Proximal extrinsic factors also play a role in the differential drive between adipose tissue depots. This review focuses on the deleterious mechanisms postulated to drive the differential metabolic response between central and lower body adipose tissue distribution.
82 citations
TL;DR: The present review will examine the phenotypic and pathophysiological differences between the different AT depots, with a particular focus on the abdominal depots and their link to metabolic complications.
Abstract: Obesity is currently the most important contributor to ill health and expenditure worldwide. More alarming is the fact that the pediatric population parallels adults, with obesity closely associated to type 2 diabetes mellitus (T2D), cardiovascular disease, hypertension, non-alcoholic fatty liver disease, vitamin D deficiency (VDD) and certain types of cancer. The observation in the early 1950s that android or truncal adipose tissue (AT) distribution compared to gynoid had a greater association with metabolic dysfunction, in particular T2D and cardiovascular disease risk, led to the hypothesis that obesity-associated complications are not associated with fat mass per se, but the pattern of fat distribution. This concept was further supported by groups of individuals with metabolic dysfunction despite a lean phenotype, and healthy obese people protected from metabolic dysfunction. It is now well recognized that an increase in visceral AT is an independent risk factor for the development of obesity-associated comorbidities with AT depot distribution, their anatomic, cellular and molecular features defining their role. The differences and the plasticity of subcutaneous, visceral and ectopic ATs to store and release fatty acids and to synthesize and secrete adipokines, defines the metabolic outcomes. The present review will examine the phenotypic and pathophysiological differences between the different AT depots, with a particular focus on the abdominal depots and their link to metabolic complications.
78 citations
TL;DR: Weight loss may improve sleep, and these improvements may promote further weight loss, and future studies should establish whether increasing sleep duration/improving sleep quality can induce weight loss.
Abstract: Data from cross-sectional and longitudinal studies have illustrated a relationship between short sleep duration (SSD) and weight gain. Individuals with SSD are heavier and gain more weight over time than normal-duration sleepers. This sleep-obesity relationship may have consequences for obesity treatments, as it appears that short sleepers have reduced ability to lose weight. Laboratory-based clinical studies found that experimental sleep restriction affects energy expenditure and intake, possibly providing a mechanistic explanation for the weight gain observed in chronic short sleepers. Specifically, compared to normal sleep duration, sleep restriction increases food intake beyond the energetic costs of increased time spent awake. Reasons for this increased energy intake after sleep restriction are unclear but may include disrupted appetite-regulating hormones, altered brain mechanisms involved in the hedonic aspects of appetite, and/or changes in sleep quality and architecture. Obstructive sleep apnea (OSA) is a disorder at the intersection of sleep and obesity, and the characteristics of the disorder illustrate many of the effects of sleep disturbances on body weight and vice versa. Specifically, while obesity is among the main risk factors for OSA, the disorder itself and its associated disturbances in sleep quality and architecture seem to alter energy balance parameters and may induce further weight gain. Several intervention trials have shown that weight loss is associated with reduced OSA severity. Thus, weight loss may improve sleep, and these improvements may promote further weight loss. Future studies should establish whether increasing sleep duration/improving sleep quality can induce weight loss.
70 citations
TL;DR: The current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism is summarized.
Abstract: Glucocorticoids (GC) and their cognate intracellular receptor, the glucocorticoid receptor (GR), have been characterised as critical checkpoints in the endocrine control of energy homeostasis in mammals. Indeed, aberrant GC action has been linked to a variety of severe metabolic diseases, including obesity, insulin resistance and type 2 diabetes. As a steroid-binding member of the nuclear receptor superfamily of transcription factors, the GR translocates into the cell nucleus upon GC binding where it serves as a transcriptional regulator of distinct GC-responsive target genes that are - in many cases - associated with glucose and lipid regulatory pathways and thereby intricately control both physiological and pathophysiological systemic energy homeostasis. Here, we summarize the current knowledge of GC/GR function in energy metabolism and systemic metabolic dysfunction, particularly focusing on glucose and lipid metabolism.
63 citations
TL;DR: Reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.
Abstract: Obesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.
46 citations
TL;DR: Assessment of the effects of thyroid hormones on the heart, and their clinical repercussions: medications such as amiodarone may induce hypothyroidism as well as hyperthyroidism (mediated by the Jod-Basedow effect).
Abstract: Thyroid hormones have a significant impact on heart function, mediated by genomic and non-genomic effects. Consequently, thyroid hormones deficit as well as excess are expected to result in profound changes in cardiac function regulation and cardiovascular hemodynamics. Thyroid hormones upregulate the expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulate the expression of phospholamban. Overall, hyperthyroidism is characterized by an increase in resting heart rate, blood volume, stroke volume, myocardial contractility, and ejection fraction. The development of "high-output heart failure" in hyperthyroidism may be due to "tachycardia-mediated cardiomyopathy." In contrast, in the hypothyroid state, thyroid hormone deficiency results in lower heart rate and weakening of myocardial contraction and relaxation, with prolonged systolic and early diastolic times. Cardiac preload is decreased owing to impaired diastolic function, cardiac afterload is increased, and chronotropic and inotropic functions are reduced. Subclinical thyroid dysfunction is relatively common in patients >65 years of age. In general, subclinical hypothyroidism increases the risk of cardiovascular heart disease (CHD) mortality and CHD events, but not of total mortality. The risk of CHD mortality and atrial fibrillation (but not other outcomes) in subclinical hyperthyroidism is higher among patients with very low levels of thyrotropin. Finally, medications such as amiodarone may induce hypothyroidism (mediated by the Wolff-Chaikoff effect) as well as hyperthyroidism (mediated by the Jod-Basedow effect). In both instances, the underlying cause is the high concentration of iodine in this medication. The purpose of this review is to assess the effects of thyroid hormones on the heart, and their clinical repercussions.
44 citations
TL;DR: This review explores how modifications in the effects of sex hormones impact on both brown and white adipose tissues and how the three pathways between adiposity, HPA and sex steroids can have a major contribution to the prevention or maintenance of obesity and therefore on overall health.
Abstract: Obesity remains a major global health concern. Understanding the metabolic influences of the obesity epidemic in the human population on maintenance of a healthy weight and metabolic profile is still of great significance. The importance and role of white adipose tissue has been long established, particularly with excess adiposity. Brown adipose tissue (BAT), however, has only recently been shown to contribute significantly to the metabolic signature of mammals outside the previously recognised role in small mammals and neonates. BAT's detection in adults has led to a renewed interest and is now considered to be a potential therapeutic target to prevent excess white fat accumulation in obesity, a theory further promoted by the recent discovery of beige fat. Adipose tissue distribution varies significantly between genders. Pre-menopausal females often show enhanced lower and peripheral fat deposition in adiposity deposition compared to the male profile of central and visceral fat accumulation with obesity. This sex disparity is partly attributed to the different effects of sex hormone profiles and interactions on the adipose tissue system. In this review, we explore this intricate relationship and show how modifications in the effects of sex hormones impact on both brown and white adipose tissues. We also discuss the impact of sex hormones on activation of the hypothalamic-pituitary-adrenal (HPA) axis and how the three pathways between adiposity, HPA and sex steroids can have a major contribution to the prevention or maintenance of obesity and therefore on overall health.
42 citations
TL;DR: Obese individuals show a decrease in the concentration of Akkermansia muciniphila in the mucus that lines the intestinal wall, resulting in thinner mucus and a weakened intestinal lining and permitting metabolic endotoxins formed by other bacterial flora like LPS to enter the blood steam and cause the chronic inflammation associated with obesity.
Abstract: While there is a large volume of literature describing a role for obesity as a risk factor for breast cancer and many other cancers, in the main a causal relationship has not been established. If the study is limited to breast cancer risk, it has been suggested that the increase in sex steroid formation that occurs in postmenopausal women plays a role. Obesity is known to be associated with chronic low grade inflammation, but no reason for this association has been offered in the past. The gut microbiome, while known to be enormous, has not in the past been considered as a metabolic role player in the body. This is now recognized to be the case. Recent studies have found the obesity is correlated with an alteration in the gut microbiome. In obese individual there is a change in the relative proportions of the two major classes of bacteria - bacteroides and firmacutes - with the latter dominant in obesity and resulting in the formation of increased amounts of metabolic endotoxins like deoxycholic acid and lipopolysaccharides (LPS). Obese individuals show a decrease in the concentration of Akkermansia muciniphila in the mucus that lines the intestinal wall, resulting in thinner mucus and a weakened intestinal lining and permitting metabolic endotoxins formed by other bacterial flora like LPS to enter the blood steam and cause the chronic inflammation associated with obesity. The change in the microbiome profile results in increases in bacterial strains that are more efficient at generating energy, leading to increased obesity. In mice, it has been shown that introducing gut bacterial flora from the cecum of obese mice into germ-free mice results in increased obesity with lesser food consumption while the reverse, introducing bacterial flora from lean mice results in a loss in weight. This raises the attractive possibility that manipulating the gut microbiome could facilitate weight loss or prevent obesity in humans.
TL;DR: Increasing evidence seems to indicate that different components such as myokines, adipokines and growth factors, released by both fat and muscle tissues, could play a key role in the regulation of skeletal health and in low bone mineral density and, thus, in osteoporosis development.
Abstract: The belief that obesity is protective against osteoporosis has recently been revised. In fact, the latest epidemiologic and clinical studies show that a high level of fat mass, but also reduced muscle mass, might be a risk factor for osteoporosis and fragility fractures. Furthermore, increasing evidence seems to indicate that different components such as myokines, adipokines and growth factors, released by both fat and muscle tissues, could play a key role in the regulation of skeletal health and in low bone mineral density and, thus, in osteoporosis development. This review considers old and recent data in the literature to further evaluate the relationship between fat, bone and muscle tissue.
TL;DR: It is hypothesized that E2 directly prevents inflammation and maintains insulin sensitivity in WAT independent of energy status using mice with similar body weights and adiposity, and directly contributed to the maintenance of insulin sensitivity during the early phase of development of metabolic dysfunction.
Abstract: Background Obesity-associated low-grade inflammation at white adipose tissue (WAT) leads to metabolic defects Sex steroid hormone estrogen may be protective against high-fat diet (HFD)-induced obesity and insulin resistance This has been tested by many previous studies utilizing rodent models of ovariectomy (OVX) and/or treatment of estradiol (E2), the major biologically active form of estrogen Body weight and adiposity are increased by OVX and reduced following E2 treatment, however Thus, the protective roles of E2 may be secondary effects to the changes in body weight and adiposity We hypothesize that E2 directly prevents inflammation and maintains insulin sensitivity in WAT independent of energy status using mice with similar body weights and adiposity Materials and methods Four groups of female C57BL/6 mice were used, including sham-operated mice treated with vehicle for E2 and fed with either a low-fat diet (LFD; Sham-Veh-LFD) or a HFD (Sham-Veh-HFD), and HFD-fed OVX mice treated with either vehicle (OVX-Veh-HFD) or E2 (OVX-E2-HFD) Body weight and abdominal parametrial WAT mass, insulin signaling, and expression levels of genes related to low-grade inflammation in WAT were compared between these groups pair-fed with equal amounts of calories for a period of 4 days Results Body weights and WAT mass were similar in all four groups OVX-Veh-HFD mice had impaired insulin signaling associated with rapid activation of inflammation, whereas OVX-E2-HFD group maintained insulin sensitivity without showing inflammation in WAT Conclusions E2 directly contributed to the maintenance of insulin sensitivity during the early phase of development of metabolic dysfunction, possibly via preventing low-grade inflammation in WAT
TL;DR: Progress made in understanding the interactions between reproduction and energy homeostasis is reviewed by focusing on the advances made to understand the cellular signaling of E2 and leptin on three neural networks: kisspeptin, pro-opiomelanocortin (POMC) and neuropeptide Y (NPY).
Abstract: The central nervous system receives hormonal cues (e.g., estrogens and leptin, among others) that influence reproduction and energy homeostasis. 17β-estradiol (E2) is known to regulate gonadotropin-releasing hormone (GnRH) secretion via classical steroid signaling and rapid non-classical membrane-initiated signaling. Because GnRH neurons are void of leptin receptors, the actions of leptin on these neurons must be indirect. Although it is clear that the arcuate nucleus of the hypothalamus is the primary site of overlap between these two systems, it is still unclear which neural network(s) participate in the cross-talk of E2 and leptin, two hormones essential for reproductive function and metabolism. Herein we review the progress made in understanding the interactions between reproduction and energy homeostasis by focusing on the advances made to understand the cellular signaling of E2 and leptin on three neural networks: kisspeptin, pro-opiomelanocortin (POMC) and neuropeptide Y (NPY). Although critical in mediating the actions of E2 and leptin, considerable work still remains to uncover how these neural networks interact in vivo.
TL;DR: The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes.
Abstract: Background A substantial body of epidemiological and experimental evidence suggests that a poor fetal and neonatal environment may "program" susceptibility in the offspring to later development of cardiovascular, renal and metabolic diseases. Materials and methods This review focuses on current knowledge from the available literature regarding the mechanisms linking an adverse developmental environment with an increased risk for cardiovascular, renal and metabolic diseases in adult life. Moreover, this review highlights important sex-dependent differences in the adaptation to developmental insults. Results Developmental programming of several diseases is secondary to changes in different mechanisms inducing important alterations in the normal development of several organs that lead to significant changes in birth weight. The different diseases occurring as a consequence of an adverse environment during development are secondary to morphological and functional cardiovascular and renal changes, to epigenetic changes and to an activation of several hormonal and regulatory systems, such as angiotensin II, sympathetic activity, nitric oxide, COX2-derived metabolites, oxidative stress and inflammation. The important sex-dependent differences in the developmental programming of diseases seem to be partly secondary to the effects of sex hormones. Recent studies have shown that the progression of these diseases is accelerated during aging in both sexes. Conclusions The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes. Future studies are needed in order to prevent the origin and reduce the incidence and consequences of developmental programmed diseases.
TL;DR: The 1,25(OH)2D3 – cellular Ca2+ – apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2 + and Ca2-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and Obesity.
Abstract: Low vitamin D status has been associated with increased risk of several cancers and obesity; concurrently, obesity and cancer have been linked to impaired vitamin D status. In both cancer and obesity, selective elimination of cancer cells and adipocytes can result in decreasing tumor size and a long-term reduction in adipose tissue mass. These effects can be achieved through induction of apoptotic cell death. The vitamin D-derived hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in epithelial cancer cells and mature adipocytes via induction of apoptotic Ca2+ signal - a sustained, prolonged increase in concentration of intracellular Ca2+. This Ca2+ signal functions as an apoptotic initiator that directly recruits apoptotic effectors, Ca2+-dependent proteases, in cancer cells and adipocytes. The 1,25(OH)2D3 - cellular Ca2+ - apoptosis link in cancer and obesity supports the rationale to include vitamin D compounds modulating intracellular Ca2+ and Ca2+-dependent apoptotic proteases as promising targets for discovery of new therapeutic and preventive agents for cancer and obesity. The concept of maintaining an increased vitamin D status for protecting against cancer and decreasing adiposity also warrants further evaluation.
TL;DR: The lack of association between adipose tissue and plasma levels of some MMPs suggests that this tissue is not a major contributor to circulating gelatinases as mentioned in this paper, and therefore, it is still necessary to go forward in the study of MMP in different metabolic situations to corroborate their role as vulnerable plaque biomarkers.
Abstract: Matrix metalloproteinases (MMPs) play an important role during physiological tissue remodeling in embryonic development and angiogenesis, as well as in pathophysiological conditions such as obesity and development and vulnerability of atherosclerotic plaque. Moreover, MMP circulating levels have emerged as potential biomarkers of cardiovascular disease. MMP expression and activity are regulated by different factors such as insulin resistance and obesity. Expanded fat tissue has been demonstrated to be an active organ, where MMPs also exert a role in adipogenesis, angiogenesis, and proliferation of extracellular matrix (ECM). However, the lack of association between adipose tissue and plasma levels of some MMPs, specifically MMP-2 and MMP-9, suggests that this tissue is not a major contributor to circulating gelatinases. MMPs are also co-expressed or co-repressed in response to inflammatory adipocytokines, like adiponectin and leptin. Adiponectin may also play a protective role in plaque rupture through selectively increasing the tissue inhibitor of metalloproteinase (TIMP) expression. Leptin induces the expression of MMP-2 activators as well as the expression of MMP-2, MMP-9, and TIMP-1 in different human cells. Furthermore, sex hormones also participate in MMP regulation. In postmenopausal women, hormone replacement therapy produces an increase in MMP activity, leading to a breakdown in ECM homeostasis and accelerated progression of vascular pathologies. Besides, in men, an inverse relationship between testosterone levels and MMP-2 activity has been described. It is still necessary to go forward in the study of MMPs in different metabolic situations to corroborate their role as vulnerable plaque biomarkers.
TL;DR: This paper summarizes a set of studies related to the potential role that therapy with GH and melatonin may play in the protection of the altered cardiac function due to aging, with a focus on experiments performed using the senescence-accelerated mouse as an aging model.
Abstract: Epidemiological studies indicate that certain aspects of lifestyle and genetics act as risk factors for a variety of cardiovascular disorders, including coronary disease, hypertension, heart failure and stroke. Aging, however, appears to be the major contributor for morbidity and mortality of the impaired cardiovascular system. Growth hormone (GH) and melatonin seem to prevent cardiac aging, as they contribute to the recovery of several physiological parameters affected by age. These hormones exhibit antioxidant properties and decrease oxidative stress and apoptosis. This paper summarizes a set of studies related to the potential role that therapy with GH and melatonin may play in the protection of the altered cardiac function due to aging, with a focus on experiments performed in our laboratory using the senescence-accelerated mouse as an aging model. In general, we observed significantly increased inflammation, oxidative stress and apoptosis markers in hearts from senescence-accelerated prone 10-month-old animals compared to 2-month-old controls, while anti-inflammatory and antiapoptotic markers as well as endothelial nitric oxide synthase were decreased. Senescence-accelerated resistant animals showed no significant changes with age. GH or melatonin treatment prevented the age-dependent cardiac alterations observed in the senescence-accelerated prone group. Combined administration of GH plus melatonin reduced the age-related changes in senescence-accelerated prone hearts in an additive fashion that was different to that displayed when administered alone. GH and melatonin may be potential agents for counteracting oxidative stress, apoptosis and inflammation in the aging heart.
TL;DR: An update of the role of leptin in reproduction is provided and its interactions with neurons, neurotransmitters and downstream targets of the reproductive axis are discussed, with a special emphasis on the actions ofptin in the central nervous system.
Abstract: Achievement of sexual maturation and maintenance of fertility in adulthood are functions that are sensitive to the metabolic status of the organism, particularly the magnitude of fat reserves. In this sense, the adipocyte-derived hormone, leptin, plays a major role in linking metabolic cues and the control of multiple neuroendocrine axes. The hypothalamus is a key site mediating leptin actions, including those involved in the modulation of the hypothalamus-pituitary-gonads (HPG) axis at different stages of development and in different environmental conditions. In the present review, we provide an update of the role of leptin in reproduction and discuss its interactions with neurons, neurotransmitters and downstream targets of the reproductive axis, with a special emphasis on the actions of leptin in the central nervous system. We hope this review will contribute to the understanding of the mechanisms whereby metabolic signals, especially leptin, influence the reproductive neuroendocrine axis modulating its activity in different nutritional states. Special attention will be given to recent advances in the identification of key hypothalamic sites and signaling pathways relevant to leptin's action in reproductive control.
TL;DR: 17β-estradiol plays a fundamental role in the regulation of Fmo3 gene transcription, as well as the inhibitory effect induced by estrogen, in an in vitro cellular system, mouse liver cells, and on the human FMO3 gene.
Abstract: Flavin-containing mono-oxygenases (FMOs) are a family of microsomal chemical- and drug-metabolizing enzymes FMO3 is a major FMO form in adult mouse and human liver FMO3 mutations have been associated with the incidence and severity of trimethylaminuria (TMAU), a metabolic disorder characterized by the inability of the affected individual to metabolize the odorous trimethylamine to its non-odorous N-oxide In addition to this primary genetic form, there are other forms of TMAU that support the hypothesis that FMO3 activity may be modulated by steroid hormones To understand the molecular mechanism involved in the regulation of Fmo3 gene expression by steroid hormones, we performed this study in an in vitro cellular system, mouse liver cells, and on the human FMO3 gene Dexamethasone, 5α-dihydrotestosterone, thyroid hormone, and progesterone had no effect on the accumulation of Fmo3 mRNA The use of increased concentration of theophylline inhibited estrogen receptor α (ERα)-mediated transcription of Fmo3 mRNA 17β-Estradiol inhibited Fmo3 mRNA accumulation The use of ICI 164,384 abolished the inhibitory effect induced by estrogen Gel-shift analyses showed a binding in the 5' region of the Fmo3 gene This binding was abrogated by an excess of a cDNA containing an estrogen-responsive element An estrogen-binding site was also present in the first intron of the human gene, as demonstrated by the gel-shift assay Supershift experiments confirmed the binding of ERα in both mouse and human samples Furthermore, chromatin immunoprecipitation assay confirmed the binding of ERα in the promoter region of mouse Fmo3 and in the first intron of the human FMO3 gene Thus, 17β-estradiol plays a fundamental role in the regulation of Fmo3 gene transcription
TL;DR: The group used sex hormone imbalance FSH receptor knock out (FORKO) female mice to recapitulate different aspects of the MetS and addressed the mechanism of visceral obesity related to metS and discover two novel sex steroid hormone-regulated deep mesenteric estrogen-dependent adipose (MEDAs) genes.
Abstract: Sex hormone imbalance is causally related with visceral adipose tissue (AT) dysfunction and visceral obesity - an etiological component of metabolic syndrome (MetS), associated with high risk of both cardiovascular disease (CVD) and type 2 diabetes. In general, premenopausal women appear to be protected from CVD and the dramatic decline in sex steroid hormone occurring during menopausal transitions or other sex-related disorders influence the regional distribution, function, and metabolism of AT and increase the risk of CVD. Visceral AT dysfunction, manifesting as abnormality of fatty acid metabolism, increased oxidative stress, endothelial dysfunction, and excessive production of adipokines have been proposed in the pathogenesis of MetS. However, direct evidence of molecular mechanisms of depot-specific AT alterations, and dysfunction causally related to MetS is limited in studies on postmenopausal women due to difficulty in collecting discrete AT specimens at different ages and repeated sampling from different fat depots. This can be overcome using animal models that can mimic the cluster of pathology leading to MetS and help establish the molecular basis of links between loss of gonadal function on various AT depots and their contribution to MetS. Our group used sex hormone imbalance FSH receptor knock out (FORKO) female mice to recapitulate different aspects of the MetS and addressed the mechanism of visceral obesity related to MetS and discover two novel sex steroid hormone-regulated deep mesenteric estrogen-dependent adipose (MEDAs) genes. Taken together, such recent studies raise hopes for pharmacologic intervention strategies targeting sex steroid hormone signaling in AT to provide protection against AT dysfunction.
TL;DR: This review focuses on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the vasculature, which underlies their potential as key regulators of vascular function.
Abstract: Crosstalk between adipose tissue and blood vessels is vital to vascular homeostasis and is disturbed in cardiovascular and metabolic diseases such as hypertension, diabetes and obesity. Cardiometabolic syndrome (CMS) refers to the clustering of obesity-related metabolic disorders such as insulin resistance, glucose and lipid profile alterations, hypertension and cardiovascular diseases. Mechanisms underlying these associations remain unclear. Adipose tissue associated with the vasculature [known as perivascular adipose tissue (PVAT)] has been shown to produce myriads of adipose tissue-derived substances called adipokines, including hormones, cytokines and reactive oxygen species (ROS), which actively participate in the regulation of vascular function and local inflammation by endocrine and/or paracrine mechanisms. As a result, the signaling from PVAT to the vasculature is emerging as a potential therapeutic target for obesity and diabetes-related vascular dysfunction. Accumulating evidence supports a shift in our understanding of the crucial role of elevated plasma levels of aldosterone in obesity, promoting insulin resistance and hypertension. In obesity, aldosterone/mineralocorticoid receptor (MR) signaling induces an abnormal secretion of adipokines, ROS production and systemic inflammation, which in turn contribute to impaired insulin signaling, reduced endothelial-mediated vasorelaxation, and associated cardiovascular abnormalities. Thus, aldosterone excess exerts detrimental metabolic and vascular effects that participate to the development of the CMS and its associated cardiovascular abnormalities. In this review, we focus on the physiopathological roles of corticosteroid receptors in the interplay between PVAT and the vasculature, which underlies their potential as key regulators of vascular function.
TL;DR: The hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones is advanced.
Abstract: 5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.
TL;DR: The current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage are reviewed.
Abstract: Obesity and excess of adipose tissue are associated with the development of cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia At the cardiac level, various morphological adaptations in cardiac structure and function occur in obese individuals Different mechanisms linking obesity to these modifications have been postulated Adipose tissue and epicardial fat releases a large number of cytokines and bioactive mediators such as leptin Leptin circulates in proportion to body fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores It participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of leptin and the different isoforms of its receptor in different tissues including the heart This hormone has distinct effects on the reproductive, cardiovascular, and immune systems; however, its role in the heart could mediate wide physiological effects observed in obese individuals Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines We herein review the current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage
TL;DR: The objective of this review is to describe what has been learned regarding the mechanisms underlying changes in regional body fat distribution that occur as a result of changes in sex hormones and to delineate effects of sex steroids in modulating body composition.
Abstract: Adult humans have a remarkable sexual dimorphism in body shape. Men tend to store relatively more fat in the upper body whereas women store more fat in the lower body. We do not have a complete understanding of the mechanisms underlying these differences, but we know that people who preferentially store abdominal fat are at greater risk of metabolic disease. It is also known that the changes in sex steroid concentrations during puberty and again with advancing age are accompanied by changes in body fat distribution. The objective of this review is to describe what has been learned regarding the mechanisms underlying changes in regional body fat distribution that occur as a result of changes in sex hormones and to delineate effects of sex steroids in modulating body composition.
TL;DR: Findings have broader implications for the study of health promotion/disease prevention in women as total adiposity and central fat distribution in accordance with changes in the hormone and metabolic milieu influence breast cancer risk, which varies by race and menopausal status.
Abstract: A sexual dimorphism exists in which increased abdominal and visceral adipose tissue (VAT) - found in women and marked by low sex hormone binding globulin (SHBG) and high bioavailable testosterone (BT) - is related to the metabolic risk profile. In men, increased BT is related to decreased abdominal obesity and a decrease in the metabolic risk profile. In women, race differences have been found in androgenic sex steroids including SHBG and BT as well as central fat distribution, creating inherently greater metabolic risk for certain populations. Estrogen and estrogen receptor isoforms play a role in fat deposition and distribution and may influence the changes that occur during the menopausal transition. Androgenic sex steroids serve a mediating role, influencing VAT accumulation and its associated metabolic risk factors while VAT also serves a mediating role influencing the androgenic sex steroid-metabolic risk relationship in women. Furthermore, androgenic sex steroids and VAT may independently contribute to the variance in several metabolic variables associated with cardiovascular disease, type 2 diabetes, and their antecedent conditions such as the metabolic syndrome. Race has been shown to modify the relationship between androgenic sex steroids and metabolic variables associated with risk for diabetes in Black and White women. Further research is warranted to examine the mechanisms involved in race differences. Total adiposity and central fat distribution in accordance with changes in the hormone and metabolic milieu influence breast cancer risk, which varies by race and menopausal status. These findings have broader implications for the study of health promotion/disease prevention in women.
TL;DR: The data suggest that estrogen maintains cellular energy stability over periods of suspended fuel acquisition and yet optimizes, by DVC AMPK-dependent mechanisms, counter-regulatory responses to metabolic challenges that occur during short-span feeding abstinence.
Abstract: Nerve cell energy status is screened within multiple classically defined hypothalamic and hindbrain components of the energy balance control network, including the hindbrain dorsal vagal complex (DVC). Signals of caudal DVC origin have a physiological role in glucostasis, e.g., maintenance of optimal supply of the critical substrate fuel, glucose, through control of motor functions such as fuel consumption and gluco-counterregulatory hormone secretion. A2 noradrenergic neurons are a likely source of these signals as combinatory laser microdissection/high-sensitivity Western blotting reveals expression of multiple biomarkers for metabolic sensing, including adenosine 5'-monophosphate-activated protein kinase (AMPK). Hypoglycemia elicits estradiol-dependent sex differences in A2 AMPK activation as phospho-AMPK (pAMPK) expression is augmented in male and ovariectomized (OVX) female, but not estrogen-replaced, OVX rats. This dichotomy may reflect, in part, estradiol-mediated up-regulation of glycolytic and tricarboxylic acid cycle enzyme expression during hypoglycemia. Our new model for short-term feeding abstinence has physiological relevance to planned (dieting) or unplanned (meal delay) interruption of consumption in modern life, which is negatively correlated with appetite control and obesity, and is useful for investigating how estrogen may mitigate the effects of disrupted fuel acquisition on energy balance via actions within the DVC. Estradiol reduces DVC AMPK activity after local delivery of the AMP mimic, 5-aminoimidazole-4-carboxamide-riboside, or cessation of feeding for 12 h but elevates pAMPK expression when these treatments are combined. These data suggest that estrogen maintains cellular energy stability over periods of suspended fuel acquisition and yet optimizes, by DVC AMPK-dependent mechanisms, counter-regulatory responses to metabolic challenges that occur during short-span feeding abstinence.
TL;DR: The results indicate an association of Per3Five repeat allele with T2DM occurrence and suggest that individuals with five repeat allele may be at a greater risk for type 2 diabetes mellitus as compared to those carrying the four repeat allele.
Abstract: Background: A number of observations support the involvement of circadian clock genes in the regulation of metabolic processes. One of these circadian genes, Per3, exhibits a variable number tandem repeat length polymorphism, consisting of two alleles, namely four and five repeat alleles, in its exon 18. The objective of this study was to examine the existence of Per3 variants in patients with type 2 diabetes mellitus (T2DM) as compared to a non T2DM control group. Methods: Intravenous blood samples were collected to obtain white blood cells from 302 T2DM patients and 330 non-diabetic, age- and sex-matched, individuals. Per3 genotyping was performed on DNA by polymerase chain reaction. Results: Frequency of five repeat allele was higher, and that of four repeat allele lower, in T2DM patients as compared to non-diabetic controls ( χ 2 = 6.977, p = 0.0082) Conclusions: The results indicate an association of Per3 five repeat allele with T2DM occurrence and suggest that individuals with five repeat allele may be at a greater risk for T2DM as compared to those carrying the four repeat allele.
TL;DR: The cross-talk between the HPA axis and AT, their relationship under stressful events, depending on steroid hormones and different adipokine secretions are examined.
Abstract: In addition to its roles in providing insulation and mechanical support, adipose tissue (AT) has been recognised as the major site for storage of surplus fuel. Since leptin was discovered, white AT (WAT) has been recognised as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. The metabolic and endocrine activities of AT are under the control of several hormones: a particular role has been played by glucocorticoids (GC), which able to participate, along with other hormones, both in recruitment of progenitor cells and in differentiation and secretive activities. AT is also able to generate cortisol from cortisone through 11β-hydroxysteroid-dehydrogenase (11β-HSD). There are controversial reports in the literature, showing a hyperactivity of 11β-HSD in obesity. It has been postulated that obesity, particularly the visceral body fat distribution (V-BFD), may be considered a maladaptation to stress exposure, thus leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and higher-than-normal cortisol levels. In this review, we will examine the cross-talk between the HPA axis and AT, their relationship under stressful events, depending on steroid hormones and different adipokine secretions.
TL;DR: A review of the relationship among these different medical situations, trying to clarify the cellular and molecular mechanisms, among obesity, sarcopenia, osteoporosis and cardiovascular diseases in the elderly.
Abstract: Aged individuals continue to increase in number, and it is important to understand the pathophysiological mechanisms of age-related changes in order to develop interventions that could contribute to "successful aging". Metabolic and hormonal factors, age-related changes in body composition, and a decline in physical activity are all involved in the tendency to lose muscle mass, to gain fat mass, and, also, to experience bone loss. Obesity, sarcopenia, and osteoporosis are important widespread health problems that lead to high prevalence of both mortality and morbidity. Indeed, during the last decades, obesity and osteoporosis have become a major health threat around the world. Aging increases the risk of developing obesity, sarcopenia, osteoporosis, and, also, cardiovascular diseases. A reduction of both bone and muscle mass with a corresponding increase of fat mass and inflammation and hormonal imbalance in the elderly lead to and may synergistically increase cardiovascular diseases. This review will focus on the relationship among these different medical situations, trying to clarify the cellular and molecular mechanisms.