Lacinová Z

Serum concentrations and tissue expression of a novel endocrine regulator fibroblast growth factor-21 in patients with type 2 diabetes and obesity.

Objective  Fibroblast growth factor‐21 (FGF21) is a novel endocrine and paracrine regulator of metabolic homeostasis. The aim of our study was to measure its serum concentrations in patients with obesity, obesity and type 2 diabetes mellitus (T2DM) and healthy subjects (C), and to assess the changes of its circulating levels and mRNA expression after dietary and pharmacological interventions.

The endocrine profile of subcutaneous and visceral adipose tissue of obese patients

The aim of the present study was to evaluate the expression profile of genes potentially related to metabolic complications of obesity in the whole adipose tissue and isolated adipocytes from subcutaneous (SAT) and visceral adipose tissue (VAT) from 12 non-diabetic obese women and 12 lean women. Real-time polymerase chain reaction was used for expression analysis of 41 genes of interest and two housekeeping genes. We found increased expression of specific proinflammatory and adipogenic genes and reduced expression of specific lipogenic and insulin signaling pathway genes in obese relative to lean women with no preferable localization in SAT or VAT depot. The gene expression significantly differed between adipocytes and adipose tissue but both contributed to the proinflammatory profile in obesity. We conclude that both SAT and VAT exhibit alterations in the expression of specific genes possibly contributing to proinflammatory and insulin resistance state and consequently to metabolic complications of obesity.

Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF-19 and FGF-21 in morbidly obese subjects

Fibroblast growth factor (FGF)‐19 and FGF‐21 are novel metabolic regulators that improve insulin resistance and obesity in rodents. The aim of the study was to assess the effects of laparoscopic sleeve gastrectomy (LSG) on serum concentrations of FGF‐19 and FGF‐21 along with circulating bile acids and other relevant hormonal and biochemical parameters.

Expression of adipokines and estrogen receptors in adipose tissue and placenta of patients with gestational diabetes mellitus

The purpose of this study was to assess the expression profile of genes with potential role in the development of insulin resistance (adipokines, cytokines/chemokines, estrogen receptors) in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and placenta of pregnant women with gestational diabetes mellitus (GDM) and age-matched women with physiological pregnancy at the time of Caesarean section. qRT-PCR was used for expression analysis of the studied genes. Leptin gene expression in VAT of GDM group was significantly higher relative to control group. Gene expressions of interleukin-6 and interleukin-8 were significantly increased, whereas the expressions of genes for estrogen receptors alpha and beta were significantly reduced in SAT of GDM group relative to controls, respectively. We found no significant differences in the expression of any genes of interest (LEP, RETN, ADIPOR1, ADIPOR2, TNF-alpha, CD68, IL-6, IL-8, ER alpha, ER beta) in placentas of women with GDM relative to controls. We conclude that increased expression of leptin in visceral adipose depot together with increased expressions of proinflammatory cytokines and reduced expressions of estrogen receptors in subcutaneous fat may play a role in the etiopathogenesis of GDM.

Novel lipidized analogs of prolactin-releasing peptide have prolonged half-lives and exert anti-obesity effects after peripheral administration.

Objectives:Obesity is a frequent metabolic disorder but an effective therapy is still scarce. Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity but are ineffective after peripheral application. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both PrRP- and PrRP-receptor-knockout mice.Results:Lipidized PrRP analogs showed binding affinity and signaling in PrRP receptor-expressing cells similar to natural PrRP. Moreover, these analogs showed high binding affinity also to anorexigenic neuropeptide FF-2 receptor. Peripheral administration of myristoylated and palmitoylated PrRP analogs to fasted mice induced strong and long-lasting anorexigenic effects and neuronal activation in the brain areas involved in food intake regulation. Two-week-long subcutaneous administration of palmitoylated PrRP31 and myristoylated PrRP20 lowered food intake, body weight and improved metabolic parameters, and attenuated lipogenesis in mice with diet-induced obesity.Conclusions:Our data suggest that the lipidization of PrRP enhances stability and mediates its effect in central nervous system. Strong anorexigenic and body-weight-reducing effects make lipidized PrRP an attractive candidate for anti-obesity treatment.

Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance

Objective:Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance.Design, subjects and methods:Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively.Results:In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P<0.0001) being also higher in mature adipocytes compared with stromo-vascular cells (P<0.0001). However, OM PEDF relative gene expression was decreased in morbidly obese subjects (P=0.01). Both OM PEDF and OM PEDF receptor (PEDFR) correlated positively with lipogenic and lipolytic genes, and with genes implicated in the lipid vacuole formation. Circulating PEDF levels were not associated with fat PEDF gene expression. In the second cohort, SC PEDF was decreased in subjects with type 2 diabetes and did not change significantly after weight loss. We next explored circulating PEDF in association with markers of liver-related insulin resistance injury (alanine aminotransferase, r=0.59, P=0.001). Interestingly, liver PEDF gene expression increased with obesity and insulin resistance in men, being significantly associated with fasting glucose and glycated hemoglobin in two independent cohorts. In fact, high glucose led to increased PEDF in HepG2 cells, while inflammatory stimuli present in the adipose tissue environment downregulated PEDF.Conclusion:Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.

Laparoscopic sleeve gastrectomy ameliorates mRNA expression of inflammation-related genes in subcutaneous adipose tissue but not in peripheral monocytes of obese patients

Low-grade inflammation links obesity, insulin resistance, and cardiovascular diseases. We investigated the effects of laparoscopic sleeve gastrectomy (LSG) on expression profile of genes involved in inflammatory pathways in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM). At baseline, obese group had significantly increased mRNA expression of proinflammatory chemokines (CCL-3, -17, -22), chemokine receptor CCR1 and cytokines (IL-10, IL-18) in SCAT and chemokine and other proinflammatory receptors (CCR-1, -2, -3, TLR-2, -4) in PM relative to control group. LSG decreased body weight, improved metabolic profile and reduced mRNA expression of up-regulated chemokine receptors, chemokines and cytokines in SCAT. In contrast, expression profiles in PM were largely unaffected by LSG. We conclude that LSG improved proinflammatory profile in subcutaneous fat but not in peripheral monocytes. The sustained proinflammatory and chemotactic profile in PM even 2 years after LSG may contribute to partial persistence of metabolic complications in obese patients after metabolic surgery.

Endocrine effects of duodenal-jejunal exclusion in obese patients with type 2 diabetes mellitus.

Duodenal-jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.

Angiopoietin-like protein 3 and 4 in obesity, type 2 diabetes mellitus, and malnutrition: the effect of weight reduction and realimentation

BackgroundAngiopoietin-like proteins (ANGPTLs) 3 and 4 are circulating factors that participate in the regulation of lipid and glucose metabolism.Subjects and methodsWe measured serum ANGPTL3 and 4 levels in 23 patients with obesity, 40 patients with obesity and type 2 diabetes mellitus (T2DM), 22 patients with anorexia nervosa (AN), 15 subjects undergoing 72-h fasting, and 12 patients with short bowel syndrome (SBS), and their changes after very-low-calorie diet (VLCD), bariatric surgery, partial realimentation, acute fasting, and parenteral nutrition in order to assess their possible role in metabolic regulations.ResultsSerum ANGPTL4 levels were higher in obese subjects without/with T2DM (94.50 ± 9.51 and 134.19 ± 7.69 vs. 50.34 ± 4.22 ng/ml, p < 0.001) and lower in subjects with AN relative to healthy control subjects (38.22 ± 4.48 vs. 65.80 ± 7.98 ng/ml, p = 0.002), while serum ANGPTL3 levels demonstrated inverse tendency. Nutritional status had no effect on ANGPTL3 and 4 mRNA expression in adipose tissue. Fasting decreased ANGPTL3 and increased ANGPTL4 levels, while VLCD reduced only ANGPTL3. Bariatric surgery and realimentation of AN or SBS patients had no effect on either ANGPTL. Multiple regression analysis identified BMI as an independent predictor of ANGPTL3; and BMI and HbA1c as independent predictors of ANGPTL4, respectively.ConclusionsTaken together, our data suggest that serum ANGPTL3 and 4 levels are influenced by nutritional status and fasting and could be involved in the metabolic disturbances present in obesity and AN.