Accumulating evidence indicates that obesity is closely associated with an increased risk of metabolic diseases such as insulin resistance, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease. Obesity results from an imbalance between food intake and energy expenditure, which leads to an excessive accumulation of adipose tissue. Adipose tissue is now recognized not only as a main site of storage of excess energy derived from food intake but also as an endocrine organ. The expansion of adipose tissue produces a number of bioactive substances, known as adipocytokines or adipokines, which trigger chronic low-grade inflammation and interact with a range of processes in many different organs. Although the precise mechanisms are still unclear, dysregulated production or secretion of these adipokines caused by excess adipose tissue and adipose tissue dysfunction can contribute to the development of obesity-related metabolic diseases. In this review, we focus on the role of several adipokines associated with obesity and the potential impact on obesity-related metabolic diseases. Multiple lines evidence provides valuable insights into the roles of adipokines in the development of obesity and its metabolic complications. Further research is still required to fully understand the mechanisms underlying the metabolic actions of a few newly identified adipokines.

Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease

In human obesity, the stroma vascular fraction (SVF) of white adipose tissue (WAT) is enriched in macrophages. These cells may contribute to low-grade inflammation and to its metabolic complications. Little is known about the effect of weight loss on macrophages and genes involved in macrophage attraction. We examined subcutaneous WAT (scWAT) of 7 lean and 17 morbidly obese subjects before and 3 months after bypass surgery. Immunomorphological changes of the number of scWAT-infiltrating macrophages were evaluated, along with concomitant changes in expression of SVF-overexpressed genes. The number of scWAT-infiltrating macrophages before surgery was higher in obese than in lean subjects (HAM56+/CD68+; 22.6 +/- 4.3 vs. 1.4 +/- 0.6%, P < 0.001). Typical "crowns" of macrophages were observed around adipocytes. Drastic weight loss resulted in a significant decrease in macrophage number (-11.63 +/- 2.3%, P < 0.001), and remaining macrophages stained positive for the anti-inflammatory protein interleukin 10. Genes involved in macrophage attraction (monocyte chemotactic protein [MCP]-1, plasminogen activator urokinase receptor [PLAUR], and colony-stimulating factor [CSF]-3) and hypoxia (hypoxia-inducible factor-1alpha [HIF-1alpha]), expression of which increases in obesity and decreases after surgery, were predominantly expressed in the SVF. We show that improvement of the inflammatory profile after weight loss is related to a reduced number of macrophages in scWAT. MCP-1, PLAUR, CSF-3, and HIF-1alpha may play roles in the attraction of macrophages in scWAT.

https://diabetes.diabetesjournals.org/content/diabetes/54/8/2277.full.pdf

Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss.

https://www.cell.com/cell-metabolism/pdf/S1550-4131(13)00111-3.pdf

Mechanisms and Metabolic Implications of Regional Differences among Fat Depots

The term matricellular proteins describes a family of structurally unrelated extracellular macromolecules that, unlike structural matrix proteins, do not play a primary role in tissue architecture, but are induced following injury and modulate cell-cell and cell-matrix interactions. When released to the matrix, matricellular proteins associate with growth factors, cytokines, and other bioactive effectors and bind to cell surface receptors transducing signaling cascades. Matricellular proteins are upregulated in the injured and remodeling heart and play an important role in regulation of inflammatory, reparative, fibrotic and angiogenic pathways. Thrombospondin (TSP)-1, -2, and -4 as well as tenascin-C and -X secreted protein acidic and rich in cysteine (SPARC), osteopontin, periostin, and members of the CCN family (including CCN1 and CCN2/connective tissue growth factor) are involved in a variety of cardiac pathophysiological conditions, including myocardial infarction, cardiac hypertrophy and fibrosis, aging-associated myocardial remodeling, myocarditis, diabetic cardiomyopathy, and valvular disease. This review discusses the properties and characteristics of the matricellular proteins and presents our current knowledge on their role in cardiac adaptation and disease. Understanding the role of matricellular proteins in myocardial pathophysiology and identification of the functional domains responsible for their actions may lead to design of peptides with therapeutic potential for patients with heart disease.

/pdf/matricellular-proteins-in-cardiac-adaptation-and-disease-3yhdan9ffh.pdf

Matricellular Proteins in Cardiac Adaptation and Disease

OBJECTIVE:To investigate whether effects on food intake are seen in obese subjects receiving exogenous administration of ghrelin.DESIGN:Randomised, double-blind, placebo-controlled study of intravenous ghrelin at doses 1 pmol/kg/min and 5 pmol/kg/min.SUBJECTS:In all, 12 healthy lean subjects (mean body mass index (BMI) 20.5±0.17 kg/m2) and 12 healthy overweight and obese subjects (mean BMI 31.9±1.02 kg/m2).MEASUREMENTS:Food intake, appetite and palatability of food, ghrelin and other obesity-related hormones, growth hormone.RESULTS:Low-dose infusion of ghrelin increased ad libitum energy intake at a buffet meal in the obese group only (mean increase 36.6±9.4%, P<0.01.) High-dose ghrelin infusion increased energy intake in both groups (mean increase 20.1±10.6% in the lean and 70.1±15.5% in the obese, P<0.01 in both cases.) Ghrelin infusion increased palatability of food in the obese group.CONCLUSION:Ghrelin increases food intake in obese as well as lean subjects. Obese people are sensitive to the appetite-stimulating effects of ghrelin and inhibition of circulating ghrelin may be a useful therapeutic target in the treatment of obesity.

Ghrelin increases food intake in obese as well as lean subjects

OBJECTIVE-Matricellular Secreted Protein, Acidic and Rich in Cysteine (SPARC), originally discovered in bone as osteonectin, is a mediator of collagen deposition and promotes fibrosis. Adipose tissue collagen has recently been found to be linked with metabolic dysregulation. Therefore, we tested the hypothesis that SPARC in human adipose tissue is influenced by glucose metabolism and adipokines. RESEARCH DESIGN AND METHODS-Serum and adipose tissue biopsies were obtained from morbidly obese nondiabetic subjects undergoing bariatric surgery and lean control subjects for analysis of metabolic markers, SPARC, and various cytokines (RT-PCR). Additionally, 24 obese subjects underwent a very-low-calorie diet of 1,883 kJ (450 kcal)/day for 16 weeks and serial subcutaneous-abdominal-adipose tissue (SCAT) biopsies (weight loss: 28 +/- 3.7 kg). Another six lean subjects underwent fast-food-based hyperalimentation for 4 weeks (weight gain: 7.2 +/- 1.6 kg). Finally, visceral adipose tissue explants were cultured with recombinant leptin, insulin, and glucose, and SPARC mRNA and protein expression determined by Western blot analyses. RESULTS-SPARC expression in human adipose tissue correlated with fat mass and was higher in SCAT. Weight, loss induced by very-low-calorie diet lowered SPARC expression by 33% and increased by 30% in adipose tissue of subjects gaining weight after a fast-food diet. SPARC expression was correlated with leptin independent of fat mass and correlated with homeostasis model assessment-insulin resistance. In vitro experiments showed that leptin and insulin potently increased SPARC production dose dependently in visceral adipose tissue explants, while glucose decreased SPARC protein. CONCLUSIONS-Our data suggest that SPARC Expression is predominant in subcutaneous fat and its expression and secretion in adipose tissue are influenced by fat mass, leptin, insulin, and glucose. The profibrotic effects of SPARC may contribute to metabolic dysregulation in obesity.

/pdf/regulation-of-the-fibrosis-and-angiogenesis-promoter-sparc-4muhz8uq9k.pdf

Regulation of the Fibrosis and Angiogenesis Promoter SPARC/Osteonectin in Human Adipose Tissue by Weight Change, Leptin, Insulin, and Glucose

To investigate a potential role for obestatin in humans by examining response to a fixed energy meal. A new anorectic peptide hormone, obestatin has recently been isolated from rat stomach. The significance of this peptide in humans is unknown. Case-control study. Hospital-based study. Nine healthy controls, nine morbidly obese subjects and eight post-gastrectomy subjects. Subjects attended after an overnight fast and were given a fixed energy meal (1550 kJ). The response of obestatin to a meal in the different groups. Fasting obestatin was significantly lower in obese subjects as compared to lean subjects (27.8±4 vs 17.2±2 pg/ml, P=0.03). Obestatin was also decreased in gastrectomy subjects but this did not reach statistical significance (27.8±4 vs 21.9±3 pg/ml, P=0.3). Obestatin did not change significantly from baseline in response to the meal. Lean and obese subjects had a similar obestatin/ghrelin ratio (0.04±0.003 vs 0.05±0.009, P=0.32), but this was higher in the gastrectomy group (0.04±0.003 vs 0.1±0.01, P<0.001). Obestatin does not vary significantly with a fixed energy meal, but is significantly lower in morbidly obese subjects as compared to lean subjects supporting a possible role for obestatin in long-term body weight regulation. Obestatin tended to be lower in gastrectomy subjects and their obestatin/ghrelin ratio differed from healthy controls. Hence, the expression of obestatin is altered following gastrectomy, suggesting other sites outside the stomach may also secrete obestatin.

Plasma obestatin levels are lower in obese and post-gastrectomy subjects, but do not change in response to a meal

Bariatric surgery (from the Greek words baros meaning 'weight' and iatrikos 'the art of healing') is a rapidly evolving branch of surgical science. The aim is to induce major weight loss in those whose obesity places them at high risk of serious health problems. In an attempt to balance the risks of surgery against the benefits of weight loss, bariatric operations are currently performed only in the morbidly obese, or those with a body mass index (BMI) > 35 kgm(-2) who already have developed comorbidity such as type 2 diabetes. Although weight loss is beneficial for obese patients with diabetes, current medical treatment for obesity is difficult. In contrast, observational studies show a major impact of bariatric surgery on diabetes, raising the question whether this approach should be used more widely to treat diabetes in obese patients? If bariatric surgery were shown to be the best way to treat diabetes in obese subjects the implications for health services would be wide-ranging. Bariatric surgery leads to withdrawal of diabetic treatment in about 60% or more of patients, and reductions of therapy for many others. Although data on bariatric surgery in subjects with diabetes are provocative, most studies have been uncontrolled or flawed in other ways. Most importantly, bariatric surgery has not yet been compared against standard medical treatment for diabetes in randomized controlled trials with diabetes-specific endpoints in all relevant patient groups. Potential indications for bariatric surgery are discussed, and the unanswered questions that need to be addressed by clinical trials are summarized. Although small numbers of patients may be interested in bariatric surgery for type 2 diabetes, current data are insufficient to endorse its wide scale use for this indication. Until essential studies are undertaken the role and economics of bariatric surgery in the diabetic clinic will remain uncertain.

Current status of bariatric surgery in the treatment of type 2 diabetes

Lack of an acute effect of ghrelin on markers of bone turnover in healthy controls and post-gastrectomy subjects.

Summary
Objective The role of retinol-binding protein-4 (RBP4) in human insulin resistance remains controversial, which may in part be explained by a gender-specific secretion of RBP4 in adipose tissue (AT). The aim of the study was to determine gender-specific depot expression of RBP4 and to identify metabolic parameters and cytokines/adipokines associated with RBP4.

Research Design and Methods  The study is an ex-vivo prospective analysis of paired AT-samples from 22 men and 26 women of similar age [men: 43·4 ± 13 (mean ± SD)years, women: 44·1 ± 12 years], BMI (men: 41·9 ± 18kg/m2, women: 38·4 ± 11kg/m2) and homeostasis model assessment of insulin resistance taken during elective surgery and ex-vivo culture using visceral-AT (VAT)-explants (n = 10). Plasma RBP4 and cytokines were measured by ELISA and mRNA expression in AT by real-time PCR. VAT-explants were cultured with recombinant leptin and insulin and RBP4 determined by western blot analyses.

Results  Overall subcutaneous AT (SCAT)-RBP4 mRNA expression was higher than VAT-expression [3·1 ± 0·26 signal units (SU; mean ± SE) vs 1·79 ± 0·18 SU, n = 48, P < 0·0001], but neither correlated with circulating RBP4. SCAT-RBP4 expression was higher in women and correlated with BMI (r = −0·5, P = 0·009) and fat mass (r = −0·5, P = 0·002). VAT-RBP4 correlated positively with GLUT-4 expression and adiponectin in men only (r = 0·54, P = 0·03 and r = 0·64, P < 0·002, respectively) when correcting for age and fat mass. Multiple regression determined leptin AT-expression as a positive predictor of AT-RBP4 in women (SCAT: β = 0·50, P = 0·002; VAT: β = 0·58, P = 0·003) and adiponectin for VAT-RBP4 in men (β = 0·69; P = 0·001). AT-RBP4 mRNA expression showed no relation with insulin resistance. Leptin stimulated RBP-4 secretion ex-vivo, whilst insulin did not affect RBP4.

Conclusion  AT-derived RBP4-mRNA expression is gender specific and regulated by leptin. Circulating RBP4 levels appear to be independent of AT-RBP4 secretion.

David Kerrigan

Papers

Regulation of the Fibrosis and Angiogenesis Promoter SPARC/Osteonectin in Human Adipose Tissue by Weight Change, Leptin, Insulin, and Glucose

Plasma obestatin levels are lower in obese and post-gastrectomy subjects, but do not change in response to a meal

Current status of bariatric surgery in the treatment of type 2 diabetes

Lack of an acute effect of ghrelin on markers of bone turnover in healthy controls and post-gastrectomy subjects.

Human RBP4 adipose tissue expression is gender specific and influenced by leptin