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Medical Specialties / Endocrinology / Obesity


Gene Therapy for Obesity: Progress and Prospects

Abstract: Advances in understanding the molecular basis of obesity and obesity-associated diseases have made gene therapy a vital approach in coping with this world-wide epidemic. Gene therapy for obesity aims to increase or decrease gene product in favor of lipolysis and energy expenditure, leading toward fat reduction and loss of body weight. It involves successful delivery and expression of therapeutic genes in appropriate cells. The ultimate goal of gene therapy is to restore and maintain energy homeostasis. Here we summarize progress made in recent years in identifying genes responsible for obesity and present examples where the gene therapy approach has been applied to treating or preventing obesity. Discussion on advantages and limitations of gene therapy strategies employed is provided. The intent of this review is to inspire further studies toward the development of new strategies for successful treatment of obesity and obesity-associated diseases. ... Read more

Adipokines: Novel Players in Rheumatic Diseases

Abstract: A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis. ... Read more

Catch It Before It Kills: Progesterone, Obesity, and the Prevention of Endometrial Cancer

Abstract: The lifetime risk for developing endometrial cancer, the fourth most common malignancy in women, is approximately 3%. Endometrial cancer is a hormone-driven cancer, with approximately 80% of endometrial cancers arising attributable to either an excess of estrogen or a lack of progesterone. In the normal endometrium, the proliferative effects of estrogen are normally countered by progesterone, but the absence of progesterone allows estrogen to induce oncogenesis, an effect that is amplified in situations of excess estrogen. One of the major emerging causes of the estrogen/progesterone imbalance is obesity. Obesity is associated with several hormonal derangements as well as dysregulation of insulin/insulin-like growth factor activity, which collectively contribute to hyperplasia and carcinogenesis in the endometrium. In this article, we provide an in-depth description of how obesity mechanistically promotes this hormone and growth factor imbalance. Given that endometrial cancer is clearly associated with obesity, we put forth the hypothesis that a large portion of these cancers might be prevented by treatment with progesterone. ... Read more

Inflammation in Aging: Cause, Effect, or Both?

Abstract: Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging: redox stress, mitochondrial damage, immunosenescence, endocrinosenescence, epigenetic modifications, and age-related diseases. However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses. Human immunodeficiency virus (HIV)-infected patients undergo a premature aging phenomenon which may provide clues to better elucidate the nature of inflammation in aging. Environmental and lifestyle effectors of inflammation may also contribute to modulation of both inflammation and age-related dysfunction. ... Read more

The Interplay of Autoimmunity and Insulin Resistance in Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is a common chronic disease characterized by selective autoimmune destruction of the pancreatic islet beta cells and subsequent dependence on exogenous insulin. Certain alleles including the high-risk HLA genotype, HLA-DR3-DQ2/DR4-DQ8, place individuals at increased risk of developing T1D. Autoantibodies to beta cell antigens are used in the diagnosis of T1D, and studies have shown that they can be used to predict risk of developing T1D in first degree relatives of probands. The annual global incidence of T1D is increasing by 3-5% per year. Many environmental factors have been implicated in the rising incidence of T1D. Proponents of the accelerator hypothesis argue that T1D and type 2 diabetes (T2D) are the same disorder of insulin resistance, although with different genetic backgrounds. While insulin resistance is a recognized hallmark of T2D, it also appears to play a significant role in the pathogenesis of T1D and its vascular complications. In this article, we will review: 1) immunogenetics of T1D, 2) risk factors for the development of islet autoimmunity and T1D, 3) mechanisms of insulin resistance in T1D, and 4) links between insulin resistance and complications in T1D. Further studies are needed to define environmental factors causing T1D as well as the role of insulin resistance in the pathogenesis of T1D and its complications. ... Read more

Inflammasome Activation in Obesity-related Inflammatory Diseases and Autoimmunity

Abstract: The inflammasome is a highly regulated protein complex that triggers caspase-1 activation and subsequent secretion of IL-1β and IL-18. Recognition of microbial components and danger signals by NOD-like receptor (NLR) family members in the cytosol promotes inflammasome activation and downstream inflammatory cytokine production. Pathogen recognition by NLRs and downstream release of inflammasome-derived cytokines are important in host defense against numerous infections. Recent studies have also identified a unique role for inflammasome regulation in the induction and pathogenesis of multiple autoimmune and inflammatory disorders. We now know that obesity-related factors and endogenous markers of cellular stress can lead to unchecked activation of the inflammasome and provoke inflammation and subsequent destruction of vital organs. This review will highlight recent findings that link inflammasome signaling to the progression of autoinflammatory and autoimmune diseases. We will focus on the contribution of inflammasome activation to the pathogenesis of autoinflammatory and autoimmune diseases that are of major significance to human health including type 2 diabetes, atherosclerosis, multiple sclerosis, and type 1 diabetes. ... Read more

Is Obstructive Sleep Apnea a Risk Factor for Diabetes?

Abstract: Obstructive sleep apnea (OSA) and type 2 diabetes are both closely related to obesity and their prevalence is increasing due to the rising average body weight in Western countries. The findings of epidemiological studies have implicated that OSA increases the risk for cardiovascular disease, and metabolic disturbances, such as insulin resistance, may link OSA to vascular morbidity. A number of observational clinical studies have evaluated the relationship between OSA and insulin resistance, suggesting an independent association. However, the confounding effect of obesity complicates the establishment of a causal relationship between OSA and insulin resistance. Potential mechanisms that may underpin this relationship were evaluated in animal and human experimental studies and include intermittent hypoxia, arousals from sleep with concomitant sympathetic activation and sleep fragmentation. Currently only three randomized controlled trials investigating the effects of OSA on insulin resistance have been published. In these trials OSA patients were randomly assigned to treatment with continuous positive airway pressure (CPAP) or subtherapeutic CPAP and treatment effects on various measures of insulin resistance were examined. In two of these trials there was no effect of CPAP on glucose metabolism and in one trial a small beneficial effect of CPAP was observed. Further carefully conducted clinical studies and randomized controlled interventional CPAP trials are needed to determine the extent to which OSA is a risk factor for diabetes and its effect on glucose metabolism. ... Read more

Ghrelin Biology and Its Role in Weight-related Disorders

Abstract: The discovery of ghrelin and its role in human metabolism has promoted significant research and advances in the study of obesity and other weight-related disorders. Ghrelin is relevant to many disorders of metabolism and weight such as obesity, cachexia, Prader-Willi Syndrome (PWS), and Anorexia Nervosa (AN), and its role in the pathophysiology differs. The changes observed in ghrelin physiology in these disorders shed light on the overall role of ghrelin in human metabolism and growth. The purpose of this review is to summarize the existing literature on ghrelin and some disorders of metabolism and growth. The disorders that will be discussed include obesity, cachexia, PWS, and AN. Within each disorder we will review relevant ghrelin physiology, recent studies, and potential modes of intervention with ghrelin analogues. ... Read more

Hormonal Interactions Between Gut and Brain

Abstract: No truly effective drugs exist to treat obesity, which is reaching pandemic proportions. The search for new treatments has led to an interest into the homeostatic system of central appetite regulation. Key components of this system include the hypothalamus and brainstem, the gut, and adipose tissue. It is now recognized that food intake leads to the release of various gut hormones. There are several anorectic (appetite suppressing) gut hormones released, including cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine, and pancreatic polypeptide. To date, only one example is known of an orexigenic (appetite stimulating) hormone, ghrelin. These hormones circulate in the blood and signal via vagal nerve afferents to communicate with the hypothalamus and brainstem. This information is integrated and processed in key hypothalamic nuclei. The arcuate nucleus appears to be a central controller of the appetite circuit, integrating both peripheral and central signals. This information is translated into downstream signals affecting body metabolism and food intake. Increased understanding and successful manipulation of this system should enable the design of a successful and much needed anti-obesity treatment. ... Read more

Bromodomain Coactivators in Cancer, Obesity, Type 2 Diabetes, and Inflammation

Abstract: Double bromodomain proteins bind to acetylated lysines in histones, bringing associated histone modification and nucleosome remodeling activity to chromatin. The ability of bromodomain regulators to alter chromatin status and control gene expression has long been appreciated to be important in the development of certain human cancers. However, bromodomain proteins have now been found also to be critical, non-redundant players in diverse, non-malignant phenotypes, directing transcriptional programs that control adipogenesis, energy metabolism and inflammation. The fact that such different processes are functionally linked by the same molecular machinery suggests a common epigenetic basis to understand and interpret the origins of several important co-morbidities, such as asthma or cancer that occurs in obesity, and complex inflammatory diseases like cardiovascular disease, systemic lupus erythematosus, rheumatoid arthritis and insulin resistance that may be built on a common pro-inflammatory foundation. ... Read more

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