Alternative renin-angiotensin system pathways in adipose tissue and their role in the pathogenesis of obesity.

Adipose tissue expresses all the renin-angiotensin system (RAS) components that play an important role in the adipogenesis, lipid and glucose metabolism regulation in an auto/paracrine manner. The classical RAS has been found to be over-activated during the adipose tissue enlargement, thus elevated generation of angiotensin II (Ang II) may contribute to the obesity pathogenesis. The contemporary view on the RAS has become more complex with the discovery of alternative pathways, including angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor, (pro)renin receptor, as well as angiotensin IV(Ang IV)/AT4 receptor. Ang-(1-7) via Mas receptor counteracts with most of the deleterious effects of the Ang II-mediated by AT1 receptor implying its beneficial role in the glucose and lipid metabolism, oxidative stress, inflammation, and insulin resistance. Pro(renin) receptor may play a role (at least partial) in the pathogenesis of the obesity by increasing the local production of Ang II in adipose tissue as well as triggering signal transduction independently of Ang II. In this review, modulation of alternative RAS pathways in adipose tissue during obesity is discussed and the involvement of Ang-(1-7), (pro)renin and AT4 receptors in the regulation of adipose tissue homeostasis and insulin resistance is summarized.

Metabolic effects of subchronic peripheral oxytocin administration in lean and obese zucker rats.

Increasing evidence indicates a role of oxytocin in controlling energy metabolism. The aim of his study was to investigate oxytocin effects on obese phenotype in leptin-resistant Zucker fatty rats, focusing on glucose and lipid metabolism. Zucker fatty rats and their lean controls were treated with oxytocin (3.6 µg/100g body weight/day) by osmotic minipumps implanted subcutaneously for 2 weeks. Two-hours intraperitoneal glucose tolerance test was performed in fasting rats. Oxytocin decreased food intake in both phenotypes while body weight gain reduced only in obese animals. In obese rats oxytocin impaired hepatic insulin extraction and enhanced liver triglyceride accumulation. Moreover, in the skeletal muscle of lean rats oxytocin treatment downregulated insulin signal transduction by decreasing of insulin receptor substrate 1 protein level and stimulating of its serine phosphorylation. Concurrently, the gene expression of insulin receptor substrate 1 in the skeletal muscle and adipose tissue was downregulated by oxytocin. In obese rats, oxytocin reduced adipocyte size and normalised mRNA levels of both fatty acid binding protein 4 and fatty acid synthase but attenuated gene expression of glucose transporter 4. The present study in Zucker fatty rats demonstrated ambivalent effects of oxytocin treatment with predominantly negative impact on skeletal muscle insulin pathway in lean animals.

Differential regulation of oxytocin receptor in various adipose tissue depots and skeletal muscle types in obese Zucker rats.

Multifunctional peptide oxytocin currently undergoes intensive research due to its proposed anti-obesity properties. Until now, little is known about regulation of oxytocin receptor in metabolically active tissues in obesity. The aim of the present study was to measure expression of oxytocin receptor upon obese phenotype with respect to the variety among adipose tissue and skeletal muscles with distinct anatomical localisation. Total homogenates were prepared from epididymal, retroperitoneal and inguinal adipose tissues as well as quadriceps and soleus muscle from lean and obese Zucker rats. Oxytocin receptor protein was determined by immunoblot. Interestingly, elevated oxytocin receptor was observed in epididymal adipose tissue of obese rats in contrast to its downregulation in subcutaneous and no change in retroperitoneal fat. In lean animals, oxytocin receptor protein was expressed at similar levels in all adipose depots. This uniformity was not observed in the case of skeletal muscle in which fibre type composition seems to be determinant of oxytocin receptor expression. Quadriceps muscle with the predominance of glycolytic fibres exhibits higher oxytocin receptor expression than almost exclusively oxidative soleus muscle. Oxytocin receptor protein levels were decreased in both skeletal muscles analysed upon obese phenotype. The present work demonstrates that even under identical endocrine circumstances, oxytocin receptor is differentially regulated in adipose tissue of obese rats depending on fat depot localisation. These results also imply which tissues may be preferentially targeted by oxytocin treatment in metabolic disease.

Aerobic training lasting for 10 weeks elevates the adipose tissue FABP4, Giα, and adiponectin expression associated by a reduced protein oxidation.

OBJECTIVE: The chronic moderate exercise positively alters the systemic glucose homeostasis, enhances the insulin action, and ameliorates the oxidative damage in the skeletal muscle and liver. The aim of this study was to investigate the effect of an intermittent aerobic training on the metabolic parameters of the white adipose tissue in the obese Zucker rats. METHODS: Obese Zucker rats, 8 week old, were subjected to running on a 4-channel treadmill (1 h/day 5 times/week 20 m/min at maximum) for 10 weeks, except the weekends, (Trained Obese Zucker, TOZ) or were placed to the turned-off treadmill (Sedentary Obese Zucker, SOZ) for the same period. The serum insulin, glucose, and triglyceride were determined. The gene expression of the renin-angiotensin system (RAS) components and selected metabolic parameters were quantified by real-time qPCR in the liver and epididymal and retroperitoneal adipose tissues. The content of the protein carbonyl groups was assayed in the liver and epididymal fat depot. RESULTS: The gene expression of the adipocyte fatty acid binding protein 4 (FABP4) was significantly elevated in the epididymal and retroperitoneal adipose tissues of the TOZ rats. The level of the adiponectin mRNA was increased in the retroperitoneal adipose tissue while leptin and inhibitory G-protein α mRNA were elevated in the epididymal adipose tissue after exercise. The aerobic training led to a decrease in the amount of protein carbonyl groups in the epididymal adipose depot. Transcription of the angiotensinogen, angiotensin-converting enzyme (ACE), and AT1 receptor genes in the epididymal adipose tissue was not influenced by the exercise. In the liver, only the AT1 receptor gene expression increased significantly. The serum glucose, insulin, and triglycerides concentrations were not changed in the TOZ rats when compared to SOZ animals. CONCLUSIONS: Data of the present study indicate that an intermittent moderate exercise in the hyperphagic obese Zucker rats lasting for 10 weeks improves some of the morphometric and metabolic parameters of the white adipose tissue and decreases the protein oxidation implying a general beneficial effect of the long-lasting exercising.

Angiotensinogen and angiotensin-converting enzyme mRNA decrease and AT1 receptor mRNA and protein increase in epididymal fat tissue accompany age-induced elevation of adiposity and reductions in expression of GLUT4 and peroxisome proliferator-activated receptor (PPARγ).

Elevated adiposity is one of the accompanying features of increased age in humans and animals. Angiotensin II (Ang II) is considered as growth promoting peptide to be involved in hypertrophic enlargement of adipose tissue. However, systemic renin-angiotensin system (RAS) seems to decrease with increased age of rats. Local adipose tissue RAS might be independent of the systemic one. Therefore we performed a comprehensive study using rats with increased age from 9 to 26 weeks and evaluated angiotensinogen, angiotensin-converting enzyme (ACE) and AT(1) receptor mRNA in epididymal adipose tissue by RT-PCR. In addition, we determined AT(1) receptor protein by Western blotting and Ang II binding. These RAS parameters were correlated with expression of selected adiposity-dependent proteins such as leptin, adiponectin, insulin-dependent glucose transporter (GLUT4) and PPARgamma. Angiotensinogen and ACE expression decreased with increased age and adiposity. On the contrary, AT(1) receptor mRNA and protein was significantly elevated in 26-week-old rats though the Ang II binding was not different between 9 and 26-week-old animals. These results suggest dynamic adaptation of local adipose tissue RAS components to increased age and adiposity most likely by decreasing local Ang II formation which is thereafter compensated by increased expression of AT(1) receptor. However, this increase in AT(1) receptor mRNA and protein is not reflected in increased receptor binding. We believe that this complex regulation of adipose tissue RAS slows down the negative age and adiposity related changes in adipose tissue leptin, adiponectin, GLUT4 and PPARgamma.

Impaired insulin secretion and uptake in patients with diffuse idiopathic skeletal hyperostosis.

OBJECTIVE: So far, high prevalence of metabolic symptoms accompanying diffuse idiopathic skeletal hyperostosis (DISH) appears not definitely elucidated because of their possible origin from other disorders such as diabetes and/or body mass differences. From such reasons this study was aimed to compare non-diabetic DISH patients to a group of age and BMI matched controls in order to distinguish the influence of DISH proper on metabolic parameters free of additional metabolic effects caused by diabetes and/or body weight differences. METHODS: Both groups of patients were subjected to oral glucose tolerance test (OGTT) and fasting serum levels of glucose, insulin, C-peptide, growth hormone, insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) were assayed. Fasting serum total cholesterol, HDL cholesterol, triglycerides, non-esterified fatty acids (NEFA) and uric acid were determined as well. The indices of insulin sensitivity and insulin secretion were calculated. RESULTS: With the exception of decreased NEFA serum level and decreased insulinogenic index and insulin/C-peptide ratio in DISH patients any other significant differences in serum parameters and indices of insulin sensitivity were not found. CONCLUSIONS: The data obtained suggest impaired beta-cell pancreatic stimulation and increased insulin hepatic extraction in DISH. It is assumed that the above mentioned conditions, if persisting for a long time, might lead to decreased ability of insulin to maintain normal serum glucose level and consequently to insulin resistance which is highly prevalent in symptomatic DISH patients.