The prevalence of obesity has increased worldwide in the past ~50 years, reaching pandemic levels. Obesity represents a major health challenge because it substantially increases the risk of diseases ...such as type 2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnoea and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages and reduced socio-economic productivity, thus increasingly creating an economic burden. Thus far, obesity prevention and treatment strategies - both at the individual and population level - have not been successful in the long term. Lifestyle and behavioural interventions aimed at reducing calorie intake and increasing energy expenditure have limited effectiveness because complex and persistent hormonal, metabolic and neurochemical adaptations defend against weight loss and promote weight regain. Reducing the obesity burden requires approaches that combine individual interventions with changes in the environment and society. Therefore, a better understanding of the remarkable regional differences in obesity prevalence and trends might help to identify societal causes of obesity and provide guidance on which are the most promising intervention strategies.
Abstract
Obesity contributes to reduced life expectancy, impaired quality of life, and disabilities, mainly in those individuals who develop cardiovascular diseases, type 2 diabetes, osteoarthritis, ...and cancer. However, there is a large variation in the individual risk to developing obesity-associated comorbid diseases that cannot simply be explained by the extent of adiposity. Observations that a proportion of individuals with obesity have a significantly lower risk for cardiometabolic abnormalities led to the concept of metabolically healthy obesity (MHO). Although there is no clear definition, normal glucose and lipid metabolism parameters—in addition to the absence of hypertension—usually serve as criteria to diagnose MHO. Biological mechanisms underlying MHO lower amounts of ectopic fat (visceral and liver), and higher leg fat deposition, expandability of subcutaneous adipose tissue, preserved insulin sensitivity, and beta-cell function as well as better cardiorespiratory fitness compared to unhealthy obesity.
Whereas the absence of metabolic abnormalities may reduce the risk of type 2 diabetes and cardiovascular diseases in metabolically healthy individuals compared to unhealthy individuals with obesity, it is still higher in comparison with healthy lean individuals. In addition, MHO seems to be a transient phenotype further justifying therapeutic weight loss attempts—even in this subgroup—which might not benefit from reducing body weight to the same extent as patients with unhealthy obesity. Metabolically healthy obesity represents a model to study mechanisms linking obesity to cardiometabolic complications. Metabolically healthy obesity should not be considered a safe condition, which does not require obesity treatment, but may guide decision-making for a personalized and risk-stratified obesity treatment.
Graphical Abstract
Graphical Abstract
The worldwide obesity epidemic has become a major health concern, because it contributes to higher mortality due to an increased risk for noncommunicable diseases including cardiovascular diseases, ...type 2 diabetes, musculoskeletal disorders and some cancers. Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood. In the past decades, data from human studies and transgenic animal models strongly suggested correlative, but also causative associations between activation of proinflammatory pathways and insulin resistance. Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance. On the other hand, adipose tissue inflammation has been shown to be essential for healthy adipose tissue expansion and remodelling. However, whether adipose tissue inflammation represents a consequence or a cause of impaired insulin sensitivity remains an open question. A better understanding of the molecular pathways linking excess adipose tissue storage to chronic inflammation and insulin resistance may provide the basis for the future development of anti-inflammatory treatment strategies to improve adverse metabolic consequences of obesity. In this review, potential mechanisms of adipose tissue inflammation and how adipose tissue inflammation may cause insulin resistance are discussed.
Obesity has become one of the major public health concerns of the past decades, because it is a key risk factor for type 2 diabetes, cardiovascular diseases, dyslipidemia, hypertension, and certain ...types of cancer, which may lead to increased mortality. Both treatment of obesity and prevention of obesity-related diseases are frequently not successful. Moreover, a subgroup of individuals with obesity does not seem to be at an increased risk for metabolic complications of obesity. In this literature, this obesity subphenotype is therefore referred to as metabolically healthy obesity (MHO). Importantly, individuals with MHO do not significantly improve their cardio-metabolic risk upon weight loss interventions and may therefore not benefit to the same extent as obese patients with metabolic comorbidities from early lifestyle, bariatric surgery, or pharmacological interventions. However, it can be debated whether MHO individuals are really healthy, especially since there is no general agreement on accepted criteria to define MHO. In addition, overall health of MHO individuals may be significantly impaired by several psycho-social factors, psychosomatic comorbidities, low fitness level, osteoarthritis, chronic pain, diseases of the respiratory system, the skin, and others. There are still open questions about predictors, biological determinants, and the mechanisms underlying MHO and whether MHO represents a transient phenotype changing with aging and behavioral and environmental factors. In this review, the prevalence, potential biological mechanisms, and the clinical relevance of MHO are discussed.
The mechanisms of how obesity contributes to the development of cardio-metabolic diseases are not entirely understood. Obesity is frequently associated with adipose tissue dysfunction, characterized ...by, e.g., adipocyte hypertrophy, ectopic fat accumulation, immune cell infiltration, and the altered secretion of adipokines. Factors secreted from adipose tissue may induce and/or maintain a local and systemic low-grade activation of the innate immune system. Attraction of macrophages into adipose tissue and altered crosstalk between macrophages, adipocytes, and other cells of adipose tissue are symptoms of metabolic inflammation. Among several secreted factors attracting immune cells to adipose tissue, chemotactic C-C motif chemokine ligand 2 (CCL2) (also described as monocyte chemoattractant protein-1 (MCP-1)) has been shown to play a crucial role in adipose tissue macrophage infiltration. In this review, we aimed to summarize and discuss the current knowledge on CCL2 with a focus on its role in linking obesity to cardio-metabolic diseases.
Abstract Prevention of obesity and therapeutic weight loss interventions have provided only limited long term success. Therefore there is an urgent need to develop novel pharmacological treatment ...strategies, which target mechanisms underlying positive energy balance, excessive fat accumulation and adverse fat distribution. Adipokines may have potential for future pharmacological treatment strategies of obesity and metabolic diseases, because they are involved in the regulation of appetite and satiety, energy expenditure, endothelial function, blood pressure, insulin sensitivity, adipogenesis, fat distribution and insulin secretion and others. There are important road blocks on the way from an adipokine candidate to the clinical use a therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, resistance to a specific adipokine, side effects of the adipokine and others. This review focuses on the potential of selected adipokines as therapeutic tools or targets and discusses important road blocks, which currently prevent their clinical use.
Obesity significantly increases the risk of developing type 2 diabetes, hypertension, coronary heart disease, stroke, fatty liver disease, dementia, obstructive sleep apnea and several types of ...cancer. Adipocyte and adipose tissue dysfunction represent primary defects in obesity and may link obesity to metabolic and cardiovascular diseases. Adipose tissue (AT) dysfunction manifests by a proinflammatory adipokine secretion pattern that mediate auto/paracrine and endocrine communication and by inflammatory cell infiltration, particularly in intra-abdominal fat. Impaired AT function is caused by the interaction of genetic, behavioral and environmental factors which lead to adipocyte hypertrophy, ectopic fat accumulation, hypoxia, AT stresses, impaired AT mitochondrial function and inflammatory processes within adipose tissue. Recently, increased autophagy has been linked to obesity and AT dysfunction and may represent a mechanism to compensate for AT stresses. A better understanding of mechanisms causing or maintaining AT dysfunction may provide new therapeutic strategies in the treatment of obesity-induced metabolic diseases.
Brown fat activates uncoupled respiration in response to cold temperature and contributes to systemic metabolic homeostasis. To date, the metabolic action of brown fat has been primarily attributed ...to its role in fuel oxidation and uncoupling protein 1 (UCP1)-mediated thermogenesis. Whether brown fat engages other tissues through secreted factors remains largely unexplored. Here we show that neuregulin 4 (Nrg4), a member of the epidermal growth factor (EGF) family of extracellular ligands, is highly expressed in adipose tissues, enriched in brown fat and markedly increased during brown adipocyte differentiation. Adipose tissue Nrg4 expression was reduced in rodent and human obesity. Gain- and loss-of-function studies in mice demonstrated that Nrg4 protects against diet-induced insulin resistance and hepatic steatosis through attenuating hepatic lipogenic signaling. Mechanistically, Nrg4 activates ErbB3 and ErbB4 signaling in hepatocytes and negatively regulates de novo lipogenesis mediated by LXR and SREBP1c in a cell-autonomous manner. These results establish Nrg4 as a brown fat-enriched endocrine factor with therapeutic potential for the treatment of obesity-associated disorders, including type 2 diabetes and nonalcoholic fatty liver disease (NAFLD).
The incidence of obesity has increased dramatically during recent decades. Obesity increases the risk for metabolic and cardiovascular diseases and may therefore contribute to premature death. With ...increasing fat mass, secretion of adipose tissue derived bioactive molecules (adipokines) changes towards a pro-inflammatory, diabetogenic and atherogenic pattern. Adipokines are involved in the regulation of appetite and satiety, energy expenditure, activity, endothelial function, hemostasis, blood pressure, insulin sensitivity, energy metabolism in insulin sensitive tissues, adipogenesis, fat distribution and insulin secretion in pancreatic β-cells. Therefore, adipokines are clinically relevant as biomarkers for fat distribution, adipose tissue function, liver fat content, insulin sensitivity, chronic inflammation and have the potential for future pharmacological treatment strategies for obesity and its related diseases. This review focuses on the clinical relevance of selected adipokines as markers or predictors of obesity related diseases and as potential therapeutic tools or targets in metabolic and cardiovascular diseases.
Serum Vaspin Concentrations in Human Obesity and Type 2 Diabetes
Byung-Soo Youn 1 2 ,
Nora Klöting 3 ,
Jürgen Kratzsch 4 ,
Namseok Lee 1 ,
Ji Woo Park 1 ,
Eun-Sun Song 1 ,
Karen Ruschke 3 ,
Andreas ...Oberbach 3 ,
Mathias Fasshauer 3 ,
Michael Stumvoll 3 and
Matthias Blüher 3
1 AdipoGen, College of Life Science and Biotechnology, Korea University, Seoul, Korea
2 Immunomodulation Research Center, University of Ulsan, Ulsan, Korea
3 Department of Medicine, University of Leipzig, Leipzig, Germany
4 Institute of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Leipzig, Germany
Address correspondence and reprint requests to Matthias Blüher, MD, University of Leipzig, Department of Medicine, Ph.-Rosenthal-Str.
27, 04103 Leipzig, Germany. E-mail: bluma{at}medizin.uni-leipzig.de ; or Byung S. Youn, PhD, Scientific Director, AdipoGen. E-mail: bsyoun{at}adipogen.com
Abstract
OBJECTIVE— Vaspin was identified as an adipokine with insulin-sensitizing effects, which is predominantly secreted from visceral adipose
tissue in a rat model of type 2 diabetes. We have recently shown that vaspin mRNA expression in adipose tissue is related
to parameters of obesity and glucose metabolism. However, the regulation of vaspin serum concentrations in human obesity and
type 2 diabetes is unknown.
RESEARCH DESIGN AND METHODS— For the measurement of vaspin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this
ELISA, we assessed circulating vaspin in a cross-sectional study of 187 subjects with a wide range of obesity, body fat distribution,
insulin sensitivity, and glucose tolerance and in 60 individuals with normal glucose tolerance (NGT), impaired glucose tolerance
(IGT), or type 2 diabetes before and after a 4-week physical training program.
RESULTS— Vaspin serum concentrations were significantly higher in female compared with male subjects. There was no difference in circulating
vaspin between individuals with NGT and type 2 diabetes. In the normal glucose-tolerant group, circulating vaspin significantly
correlated with BMI and insulin sensitivity. Moreover, physical training for 4 weeks resulted in significantly increased circulating
vaspin levels.
CONCLUSIONS— We found a sexual dimorphism in circulating vaspin. Elevated vaspin serum concentrations are associated with obesity and
impaired insulin sensitivity, whereas type 2 diabetes seems to abrogate the correlation between increased circulating vaspin,
higher body weight, and decreased insulin sensitivity. Low circulating vaspin correlates with a high fitness level, whereas
physical training in untrained individuals causes increased vaspin serum concentrations.
ELISA, enzyme-linked immunosorbent assay
HEK, human embryonic kidney
IGT, impaired glucose tolerance
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
PAI-1, plasminogen activator inhibitor type 1
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 8 November 2007. DOI: 10.2337/db07-1045.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1045 .
B.-S.Y. and N.K. contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 3, 2007.
Received July 28, 2007.
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