In a society where physical activity is limited and food supply is abundant, metabolic diseases are becoming a serious epidemic. Metabolic syndrome (MetS) represents a cluster of metabolically related symptoms such as obesity, hypertension, dyslipidemia, and carbohydrate intolerance, and significantly increases type 2 diabetes mellitus risk. Insulin resistance and hyperinsulinemia are consistent characteristics of MetS, but which of these features is the initiating insult is still widely debated. Regardless, both of these conditions trigger adverse responses from the pancreatic β cell, which is responsible for producing, storing, and releasing insulin to maintain glucose homeostasis. The observation that the degree of β cell dysfunction correlates with the severity of MetS highlights the need to better understand β cell dysfunction in the development of MetS. This Review focuses on the current understanding from rodent and human studies of the progression of β cell responses during the development of MetS, as well as recent findings addressing the complexity of β cell identity and heterogeneity within the islet during disease progression. The differential responses observed in β cells together with the heterogeneity in disease phenotypes within the patient population emphasize the need to better understand the mechanisms behind β cell adaptation, identity, and dysfunction in MetS.
Laura I. Hudish, Jane E.B. Reusch, Lori Sussel
The distribution of telomere length in humans is broad, but it has finite upper and lower boundaries. Growing evidence shows that there are disease processes that are caused by both short and long telomere length extremes. The genetic basis of these short and long telomere syndromes may be linked to mutations in the same genes, such as the telomerase reverse transcriptase (TERT), but through differential effects on telomere length. Short telomere syndromes have a predominant degenerative phenotype marked by organ failure that most commonly manifests as pulmonary fibrosis and are associated with a relatively low cancer incidence. In contrast, insights from studies of cancer-prone families as well as genome-wide association studies (GWAS) have identified both rare and common variants that lengthen telomeres as being strongly associated with cancer risk. We have hopothesized that these cancers represent a long telomere syndrome that is associated with a high penetrance of cutaneous melanoma and chronic lymphocytic leukemia. In this Review, we will synthesize the clinical and human genetic observations with data from mouse models to define the role of telomeres in cancer etiology and biology.
Emily J. McNally, Paz J. Luncsford, Mary Armanios
The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae.
Kerstin Stemmer, Timo D. Müller, Richard D. DiMarchi, Paul T. Pfluger, Matthias H. Tschöp
Lipodystrophies are the result of a range of inherited and acquired causes, but all are characterized by perturbations in white adipose tissue function and, in many instances, its mass or distribution. Though patients are often nonobese, they typically manifest a severe form of the metabolic syndrome, highlighting the importance of white fat in the “safe” storage of surplus energy. Understanding the molecular pathophysiology of congenital lipodystrophies has yielded useful insights into the biology of adipocytes and informed therapeutic strategies. More recently, genome-wide association studies focused on insulin resistance have linked common variants to genes implicated in adipose biology and suggested that subtle forms of lipodystrophy contribute to cardiometabolic disease risk at a population level. These observations underpin the use of aligned treatment strategies in insulin-resistant obese and lipodystrophic patients, the major goal being to alleviate the energetic burden on adipose tissue.
Jake P. Mann, David B. Savage
Skin and intestinal epithelial barriers play a pivotal role in protecting underlying tissues from harsh external environments. The protective role of these epithelia is, in part, dependent on a remarkable capacity to restore barrier function and tissue homeostasis after injury. In response to damage, epithelial wounds repair by a series of events that integrate epithelial responses with those of resident and infiltrating immune cells including neutrophils and monocytes/macrophages. Compromise of this complex interplay predisposes to development of chronic nonhealing wounds, contributing to morbidity and mortality of many diseases. Improved understanding of crosstalk between epithelial and immune cells during wound repair is necessary for development of better pro-resolving strategies to treat debilitating complications of disorders ranging from inflammatory bowel disease to diabetes. In this Review we focus on epithelial and innate immune cell interactions that mediate wound healing and restoration of tissue homeostasis in the skin and intestine.
Jennifer C. Brazil, Miguel Quiros, Asma Nusrat, Charles A. Parkos
Immune cells are pivotal in the reaction to injury, whereupon, under ideal conditions, repair and resolution phases restore homeostasis following initial acute inflammation. Immune cell activation and reprogramming require transcriptional changes that can only be initiated if epigenetic alterations occur. Recently, accelerated deciphering of epigenetic mechanisms has extended knowledge of epigenetic regulation, including long-distance chromatin remodeling, DNA methylation, posttranslational histone modifications, and involvement of small and long noncoding RNAs. Epigenetic changes have been linked to aspects of immune cell development, activation, and differentiation. Furthermore, genome-wide epigenetic landscapes have been established for some immune cells, including tissue-resident macrophages, and blood-derived cells including T cells. The epigenetic mechanisms underlying developmental steps from hematopoietic stem cells to fully differentiated immune cells led to development of epigenetic technologies and insights into general rules of epigenetic regulation. Compared with more advanced research areas, epigenetic reprogramming of immune cells in injury remains in its infancy. While the early epigenetic mechanisms supporting activation of the immune response to injury have been studied, less is known about resolution and repair phases and cell type–specific changes. We review prominent recent findings concerning injury-mediated epigenetic reprogramming, particularly in stroke and myocardial infarction. Lastly, we illustrate how single-cell technologies will be crucial to understanding epigenetic reprogramming in the complex sequential processes following injury.
Katarzyna Placek, Joachim L. Schultze, Anna C. Aschenbrenner
The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.
Mario M. Zaiss, Rheinallt M. Jones, Georg Schett, Roberto Pacifici
Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells’ dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
Acute organ injuries such as acute cerebrovascular accidents, myocardial infarction, acute kidney injury, acute lung injury, and others are among the leading causes of death worldwide. Dysregulated or insufficient organ repair mechanisms limit restoration of homeostasis and contribute to chronic organ failure. Studies reveal that both humans and mice harness potent non-stem cells that are capable of directly or indirectly promoting tissue repair. Specific populations of T lymphocytes have emerged as important reparative cells with context-specific actions. These T cells can resolve inflammation and secrete reparative cytokines and growth factors as well as interact with other immune and stromal cells to promote the complex and active process of tissue repair. This Review focuses on the major populations of T lymphocytes known to mediate tissue repair, their reparative mechanisms, and the diseases in which they have been implicated. Elucidating and harnessing the mechanisms that promote the reparative functions of these T cells could greatly improve organ dysfunction after acute injury.
Franco R. D’Alessio, Johanna T. Kurzhagen, Hamid Rabb
Neutrophils are the most abundant immune cells in humans and serve as first responders to a myriad of host perturbations. Equipped with a plethora of antimicrobial molecules, neutrophils invade sites of inflammation to eradicate pathogens and clear debris. Traditionally, neutrophils were thought to cause collateral tissue damage before dying at the site. However, the presence of neutrophil infiltration into sterile injuries (in the absence of infections) suggests additional roles for these cells. Now, the view of neutrophils as indiscriminate killers seems to be changing as evolving evidence suggests that neutrophils actively orchestrate resolution of inflammation and contribute to tissue repair. Novel concepts include the idea that neutrophils are key to revascularization and subsequently reverse-transmigrate back to the vasculature, actively leaving sites of tissue damage to re-home to functional niches in the lung and bone marrow. This Review scrutinizes the role of neutrophils in tissue damage and repair, discussing recent findings and raising unresolved questions around this intriguing immune cell.
Moritz Peiseler, Paul Kubes
No posts were found with this tag.