Dysregulation of epicardial adipose tissue in cachexia due to heart failure. the role of natriuretic peptides and cardiolipin

Background: Cachexia worsens long-term prognosis of patients with heart failure (HF). Effective treatment of cachexia is missing. We seek to characterize mechanisms of cachexia in adipose tissue, which could serve as novel targets for the treatment. Methods: The study was conducted in advanced HF patients (n = 52; 83% male patients) undergoing heart transplantation. Patients with ≥7.5% non-intentional body weight (BW) loss during the last 6 months were rated cachectic. Clinical characteristics and circulating markers were compared between cachectic (n = 17) and the remaining, BW-stable patients. In epicardial adipose tissue (EAT), expression of selected genes was evaluated, and a combined metabolomic/lipidomic analysis was performed to assess (i) the role of adipose tissue metabolism in the development of cachexia and (ii) potential impact of cachexia-associated changes on EAT-myocardium environment. Results: Cachectic vs. BW-stable patients had higher plasma levels of natriuretic peptide B (BNP; 2007 ± 1229 vs. 1411 ± 1272 pg/mL; P = 0.010) and lower EAT thickness (2.1 ± 0.8 vs. 2.9 ± 1.4 mm; P = 0.010), and they were treated with ~2.5-fold lower dose of both β-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACE/ARB-inhibitors). The overall pattern of EAT gene expression suggested simultaneous activation of lipolysis and lipogenesis in cachexia. Lower ratio between expression levels of natriuretic peptide receptors C and A was observed in cachectic vs. BW-stable patients (0.47 vs. 1.30), supporting activation of EAT lipolysis by natriuretic peptides. Fundamental differences in metabolome/lipidome between BW-stable and cachectic patients were found. Mitochondrial phospholipid cardiolipin (CL), specifically the least abundant CL 70:6 species (containing C16:1, C18:1, and C18:2 acyls), was the most discriminating analyte (partial least squares discriminant analysis; variable importance in projection score = 4). Its EAT levels were higher in cachectic as compared with BW-stable patients and correlated with the degree of BW loss during the last 6 months (r = −0.94; P = 0.036). Conclusions: Our results suggest that (i) BNP signalling contributes to changes in EAT metabolism in cardiac cachexia and (ii) maintenance of stable BW and ‘healthy’ EAT-myocardium microenvironment depends on the ability to tolerate higher doses of both ACE/ARB inhibitors and β-adrenergic blockers. In line with preclinical studies, we show for the first time in humans the association of cachexia with increased adipose tissue levels of CL. Specifically, CL 70:6 could precipitate wasting of adipose tissue, and thus, it could represent a therapeutic target to ameliorate cachexia

Combined intervention with pioglitazone and n-3 fatty acids in metformin-treated type 2 diabetic patients: improvement of lipid metabolism

Background: The marine n-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exert numerous beneficial effects on health, but their potency to improve treatment of type 2 diabetic (T2D) patients remains poorly characterized. We aimed to evaluate the effect of a combination intervention using EPA?+?DHA and the insulin-sensitizing drug pioglitazone in overweight/obese T2D patients already treated with metformin.Methods: In a parallel-group, four-arm, randomized trial, 69 patients (66 % men) were assigned to 24-week-intervention using: (i) corn oil (5 g/day; Placebo), (ii) pioglitazone (15 mg/day; Pio), (iii) EPA?+?DHA concentrate (5 g/day, containing ~2.8 g EPA?+?DHA; Omega-3), or (iv) pioglitazone and EPA?+?DHA concentrate (Pio&amp; Omega-3). Data from 60 patients were used for the final evaluation. At baseline and after intervention, various metabolic markers, adiponectin and cytokines were evaluated in serum using standard procedures, EPA?+?DHA content in serum phospholipids was evaluated using shotgun lipidomics and mass spectrometry, and hyperinsulinemic-euglycemic clamp and meal test were also performed. Indirect calorimetry was conducted after the intervention. Primary endpoints were changes from baseline in insulin sensitivity evaluated using hyperinsulinemic-euglycemic clamp and in serum triacylglycerol concentrations in fasting state. Secondary endpoints included changes in fasting glycemia and glycated hemoglobin (HbA1c), changes in postprandial glucose, free fatty acid and triacylglycerol concentrations, metabolic flexibility assessed by indirect calorimetry, and inflammatory markers.Results: Omega-3 and Pio&amp; Omega-3 increased EPA?+?DHA content in serum phospholipids. Pio and Pio&amp; Omega-3 increased body weight and adiponectin levels. Both fasting glycemia and HbA1c were increased by Omega-3, but were unchanged by Pio&amp; Omega-3. Insulin sensitivity was not affected by Omega-3, while it was improved by Pio&amp; Omega-3. Fasting triacylglycerol concentrations and inflammatory markers were not significantly affected by any of the interventions. Lipid metabolism in the meal test and metabolic flexibility were additively improved by Pio&amp; Omega-3.Conclusion: Besides preventing a modest negative effect of n-3 fatty acids on glycemic control, the combination of pioglitazone and EPA?+?DHA can be used to improve lipid metabolism in T2D patients on stable metformin therapy.Trial registration: EudraCT number 2009-011106-42.<br/

Neudesin in obesity and type 2 diabetes mellitus: the effect of acute fasting and weight reducing interventions

Helena Kratochvilova,1&ndash;3 Zdenka Lacinova,1&ndash;3 Jana Klouckova,1&ndash;3 Petra Kavalkova,2,3 Anna Cinkajzlova,1&ndash;3 Pavel Trachta,4 Jarmila Krizova,4 Marek Benes,5 Karin Dolezalova,6 Martin Fried,6 Zuzana Vlasakova,7 Terezie Pelikanova,7 Julius Spicak,5 Milos Mraz,2,3,7 Martin Haluzik1&ndash;3,7 1Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2Department of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic; 3Department of Medical Biochemistry and Laboratory Diagnostics, General University Hospital, Prague, Czech Republic; 4Third Department of Medicine, Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; 5Hepatogastroenterology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 6Department of Surgery, OB Clinic, Prague, Czech Republic; 7Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Context: Neudesin has recently been identified as a novel regulator of energy expenditure in experimental animals; however, its role in humans remains unexplored.Objective: The aim of this study was to assess the effects of obesity and type 2 diabetes mellitus (T2DM) along with selected weight reducing interventions on serum neudesin levels and adipose tissue mRNA expression.Patients and methods: Fifteen obese subjects with T2DM undergoing endoscopic duodenal-jejunal bypass liner (DJBL) implantation, 17 obese subjects (11 with T2DM, 6 without T2DM) scheduled for gastric plication (GP), 15 subjects with functional hypoglycemia subjected to 72-hour acute fasting (AF), and 12 healthy controls were included in the study.Results: Baseline neudesin levels were comparable between all groups. DJBL increased neudesin at 6 and 10 months after the procedure (1.77&plusmn;0.86 vs 2.28&plusmn;1.27 vs 2.13&plusmn;1.02 ng/mL, P=0.001 for baseline vs 6&nbsp;vs 10 months) along with reduction in body weight and improvement of HbA1c without any effect on neudesin mRNA expression in subcutaneous adipose tissue. Conversely, GP did not affect neudesin levels despite marked reduction in body weight and improvement of HbA1c. In contrast, AF decreased neudesin levels during the entire period (1.74&plusmn;0.54 vs 1.46&plusmn;0.48 ng/mL, P=0.001 for baseline vs 72 hours) with no impact of subsequent re-alimentation on neudesin concentrations.Conclusion: Neudesin levels are differentially regulated during AF and chronic weight reduction induced by DJBL or GP. Further studies are needed to assess its possible significance in energy homeostasis regulation in humans. Keywords: neudesin, obesity, type 2 diabetes mellitus, bariatric surgery, acute fasting, weight reduction, energy homeostasi