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American Journal of Physiology. Cell... Mar 2021Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease... (Review)
Review
Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.
Topics: Adipocytes; Adipose Tissue; Animals; Cytokines; Humans; Inflammation; Metabolic Diseases; Obesity
PubMed: 33356944
DOI: 10.1152/ajpcell.00379.2020 -
Cell Metabolism Dec 2021Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added... (Review)
Review
Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess, these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which excessive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options for the treatment of metabolic disease based upon this knowledge.
Topics: Diet; Fructose; Glucose; Humans; Liver; Metabolic Diseases; Obesity
PubMed: 34619074
DOI: 10.1016/j.cmet.2021.09.010 -
Genes & Development Mar 2021Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized... (Review)
Review
Obesity is the most common cause of insulin resistance, and the current obesity epidemic is driving a parallel rise in the incidence of T2DM. It is now widely recognized that chronic, subacute tissue inflammation is a major etiologic component of the pathogenesis of insulin resistance and metabolic dysfunction in obesity. Here, we summarize recent advances in our understanding of immunometabolism. We discuss the characteristics of chronic inflammation in the major metabolic tissues and how obesity triggers these events, including a focus on the role of adipose tissue hypoxia and macrophage-derived exosomes. Last, we also review current and potential new therapeutic strategies based on immunomodulation.
Topics: Adipose Tissue; Cell Hypoxia; Chronic Disease; Exosomes; Humans; Immunomodulation; Inflammation; Metabolic Diseases
PubMed: 33649162
DOI: 10.1101/gad.346312.120 -
Cell Metabolism Dec 2014Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have... (Review)
Review
Accumulation of DNA damage has been linked to the process of aging and to the onset of age-related diseases including diabetes. Studies on progeroid syndromes have suggested that the DNA damage response is involved in regulation of metabolic homeostasis. DNA damage could impair metabolic organ functions by causing cell death or senescence. DNA damage also could induce tissue inflammation that disturbs the homeostasis of systemic metabolism. Various roles of molecules related to DNA repair in cellular metabolism are being uncovered, and such molecules could also have an impact on systemic metabolism. This review explores mechanisms by which the DNA damage response could contribute to metabolic dysfunction.
Topics: Animals; DNA Damage; DNA Repair; Humans; Metabolic Diseases
PubMed: 25456739
DOI: 10.1016/j.cmet.2014.10.008 -
Cell Metabolism Mar 2023Global estimates of prevalence, deaths, and disability-adjusted life years (DALYs) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were...
Global estimates of prevalence, deaths, and disability-adjusted life years (DALYs) from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 were examined for metabolic diseases (type 2 diabetes mellitus [T2DM], hypertension, and non-alcoholic fatty liver disease [NAFLD]). For metabolic risk factors (hyperlipidemia and obesity), estimates were limited to mortality and DALYs. From 2000 to 2019, prevalence rates increased for all metabolic diseases, with the greatest increase in high socio-demographic index (SDI) countries. Mortality rates decreased over time in hyperlipidemia, hypertension, and NAFLD, but not in T2DM and obesity. The highest mortality was found in the World Health Organization Eastern Mediterranean region, and low to low-middle SDI countries. The global prevalence of metabolic diseases has risen over the past two decades regardless of SDI. Urgent attention is needed to address the unchanging mortality rates attributed to metabolic disease and the entrenched sex-regional-socioeconomic disparities in mortality.
Topics: Humans; Quality-Adjusted Life Years; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Global Burden of Disease; Risk Factors; Obesity; Hypertension; Metabolic Diseases
PubMed: 36889281
DOI: 10.1016/j.cmet.2023.02.003 -
Cell Metabolism Jul 2021The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as... (Review)
Review
The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. This review discusses the current understanding of how ceramide regulates signaling and metabolic pathways to exacerbate metabolic diseases and the Janus faces for its further metabolite S1P, the kinases that produce it, and the multifaceted and at times opposing actions of S1P receptors in various tissues. Gaps and limitations in current knowledge are highlighted together with the need to further decipher the full array of their actions in tissue dysfunction underlying metabolic pathologies, pointing out prospects to move this young field of research toward the development of effective therapeutics.
Topics: Animals; Humans; Lipid Metabolism; Metabolic Diseases; Metabolic Networks and Pathways; Obesity; Sphingolipids
PubMed: 34233172
DOI: 10.1016/j.cmet.2021.06.006 -
Frontiers in Endocrinology 2023Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic...
Insulin resistance (IR) plays a crucial role in the development and progression of metabolism-related diseases such as diabetes, hypertension, tumors, and nonalcoholic fatty liver disease, and provides the basis for a common understanding of these chronic diseases. In this study, we provide a systematic review of the causes, mechanisms, and treatments of IR. The pathogenesis of IR depends on genetics, obesity, age, disease, and drug effects. Mechanistically, any factor leading to abnormalities in the insulin signaling pathway leads to the development of IR in the host, including insulin receptor abnormalities, disturbances in the internal environment (regarding inflammation, hypoxia, lipotoxicity, and immunity), metabolic function of the liver and organelles, and other abnormalities. The available therapeutic strategies for IR are mainly exercise and dietary habit improvement, and chemotherapy based on biguanides and glucagon-like peptide-1, and traditional Chinese medicine treatments (e.g., herbs and acupuncture) can also be helpful. Based on the current understanding of IR mechanisms, there are still some vacancies to follow up and consider, and there is also a need to define more precise biomarkers for different chronic diseases and lifestyle interventions, and to explore natural or synthetic drugs targeting IR treatment. This could enable the treatment of patients with multiple combined metabolic diseases, with the aim of treating the disease holistically to reduce healthcare expenditures and to improve the quality of life of patients to some extent.
Topics: Insulin Resistance; Humans; Chronic Disease; Signal Transduction; Metabolic Diseases; Receptor, Insulin
PubMed: 37056675
DOI: 10.3389/fendo.2023.1149239 -
Cold Spring Harbor Perspectives in... Sep 2012Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in... (Review)
Review
Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.
Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue; Animals; Gene Regulatory Networks; Humans; Metabolic Diseases; Models, Biological; Signal Transduction
PubMed: 22952395
DOI: 10.1101/cshperspect.a008417 -
Molecular Metabolism Aug 2021
Topics: Animals; Disease Models, Animal; Humans; Liver; Metabolic Diseases; Non-alcoholic Fatty Liver Disease
PubMed: 34229990
DOI: 10.1016/j.molmet.2021.101274 -
Journal of Internal Medicine Nov 2018Many of the comorbidities of obesity, including type 2 diabetes and cardiovascular diseases, are related to the low-grade chronic inflammation of white adipose tissue.... (Review)
Review
Many of the comorbidities of obesity, including type 2 diabetes and cardiovascular diseases, are related to the low-grade chronic inflammation of white adipose tissue. Under white adipocyte stress, local infiltration of immune cells and enhanced production of pro-inflammatory cytokines together reduce metabolic flexibility and lead to insulin resistance in obesity. Whereas white adipocytes act in energy storage, brown and beige adipocytes specialize in energy expenditure. Brown and beige activity protects against obesity and associated metabolic disorders, such as hyperglycaemia and hyperlipidaemia. Compared to white fat, brown adipose tissue depots are less susceptible to developing local inflammation in response to obesity; however, strong obesogenic insults ultimately induce a locally pro-inflammatory environment in brown fat. This condition directly alters the thermogenic activity of brown fat by impairing its energy expenditure mechanism and uptake of glucose for use as a fuel substrate. Pro-inflammatory cytokines also impair beige adipogenesis, which occurs mainly in subcutaneous adipose tissue. There is evidence that inflammatory processes occurring in perivascular adipose tissues alter their brown-versus-white plasticity, impair the extent of browning in these depots and favour the local release of vasculature damaging signals. In summary, the targeting of brown and beige adipose tissues by pro-inflammatory signals and the subsequent impairment of their thermogenic and metabolite draining activities appears to represent obesity-driven disturbances that contribute to metabolic syndrome and cardiovascular alterations in obesity.
Topics: Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Humans; Inflammation; Metabolic Diseases; Obesity
PubMed: 29923291
DOI: 10.1111/joim.12803