Thomas Bobbert

Adiponectin Does Not Cross the Blood-Brain Barrier but Modifies Cytokine Expression of Brain Endothelial Cells

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism.

Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21

OBJECTIVE Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

Fibroblast growth factor 21 predicts the metabolic syndrome and type 2 diabetes in Caucasians.

OBJECTIVE The incidence of the metabolic syndrome and type 2 diabetes mellitus (T2DM) is rising worldwide. Liver-derived fibroblast growth factor (FGF)-21 affects glucose and lipid metabolism. The aim of this study was to analyze the predictive value of FGF-21 on the incidence of T2DM and the metabolic syndrome. RESEARCH DESIGN AND METHODS The Metabolic Syndrome Berlin Potsdam (MeSyBePo) recall study includes 440 individuals. Glucose metabolism was analyzed using an oral glucose tolerance test, including insulin measurements. FGF-21 was measured using enzyme-linked immunosorbent assay. Primary study outcome was diabetes and the metabolic syndrome incidence and change of glucose subtraits. RESULTS During a mean follow-up of 5.30 ± 0.1 years, 54 individuals developed the metabolic syndrome, 35 developed T2DM, and 69 with normal glucose tolerance at baseline progressed to impaired glucose metabolism, defined as impaired fasting glucose, impaired glucose tolerance, or T2DM. FGF-21 predicted incident metabolic syndrome (lnFGF-21 odds ratio [OR] 2.6 [95% CI 1.5 – 4.5]; P = 0.001), T2DM (2.4 [1.2–4.7]; P = 0.01), and progression to impaired glucose metabolism (2.2 [1.3 – 3.6]; P = 0.002) after adjustment for age, sex, BMI, and follow-up time. Additional adjustment for waist-to-hip ratio, systolic blood pressure, HDL cholesterol, triglycerides, and fasting glucose did not substantially modify the predictive value of FGF-21. CONCLUSIONS FGF-21 is an independent predictor of the metabolic syndrome and T2DM in apparently healthy Caucasians. These results may indicate FGF-21 resistance precedes the onset of the metabolic syndrome and T2DM.

Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness.

OBJECTIVE Retinol is transported in a complex with retinol-binding protein 4 (RBP4) and transthyretin (TTR) in the circulation. While retinol is associated with various cardiovascular risk factors, the relation between retinol, RBP4, TTR and carotid intima media thickness (IMT) has not been analysed yet. METHODS Retinol, RBP4 and TTR were measured in 96 individuals and their relation to mean and maximal IMT was determined. RESULTS Mean IMT correlated with RBP4 (r=0.335, p<0.001), retinol (r=-0.241, p=0.043), RBP/TTR ratio (r=0.254, p=0.025) and retinol/RBP4 ratio (r=-0.549, p<0.001). Adjustment for age, sex, BMI, blood pressure, HDL/total cholesterol ratio, triglyceride, diabetes and smoking revealed that the retinol/RBP4 ratio was strongly and independently associated with mean IMT. Similar results were found for maximal IMT, which included the measurement of plaques. CONCLUSION The data support that the transport complex of vitamin A is associated with the IMT, an established parameter of atherosclerosis. Changes in RBP4 saturation with retinol may link renal dysfunction and insulin resistance to atherosclerosis.

Relation between fibroblast growth factor–21, adiposity, metabolism, and weight reduction☆

Fibroblast growth factor-21 (FGF-21) has been proposed as a novel metabolic regulator, and animal experiments suggested that FGF-21 may affect energy balance. In humans, FGF-21 was correlated with obesity. Until now, no data exist regarding the relationship of FGF-21 and weight reduction in humans. We therefore investigated whether FGF-21 is modified by a moderate intended weight loss in a human trial. Thirty obese individuals (24 female, 6 male) participated in a weight reduction program for 6 months. In addition to several anthropometric and metabolic parameters, FGF-21 was measured before and after weight loss. Baseline serum FGF-21 was independently associated with markers of lipid metabolism and waist circumference. The multimodal intervention induced a moderate weight loss (97.4 ± 3.1 vs 92.2 ± 3.1 kg, P < .001), which was accompanied by a significant improvement of lipid and glucose metabolism. However, FGF-21 levels were not modified by moderate weight reduction; and FGF-21 levels at baseline were not a predictive marker for subsequent weight loss. The results presented here confirmed that FGF-21 levels are associated with markers of lipid metabolism and an estimate of abdominal adiposity. The finding that moderate weight loss did not induce changes of FGF-21 levels in humans suggests that FGF-21 is not directly regulated by fat mass under those conditions.

Effects of pronounced weight loss on Adiponectin oligomer composition and metabolic parameters

Objective: Adiponectin is an adipocytokine secreted into circulation in three isoforms. The aim of the study was to investigate changes of adiponectin isoforms during profound weight loss and its relation to anthropomorphometric and metabolic parameters.

Physiological modulation of circulating FGF21: relevance of free fatty acids and insulin

Fibroblast growth factor 21 (FGF-21), a novel metabolic factor in obesity and fasting metabolism, has been shown to be regulated by supraphysiological levels of free fatty acids (FFAs) under hyperinsulinemic conditions. Interestingly, it is still unclear whether the observed effects of FFAs on FGF-21 are relevant under physiological conditions, and the relative functions of FFAs and insulin within this context also need to be determined. Fourteen healthy men were studied in a randomized controlled crossover trial (RCT) using lipid heparin infusion (LHI) at a dose inducing physiological elevations of FFAs vs. saline heparin infusion. In a second randomized controlled trial, FGF-21 was analyzed in 14 patients with type 1 diabetes (6 men, 8 women) during continuous insulin supply vs. discontinued insulin infusion and subsequently increased lipolysis and ketosis. Circulating FGF-21 increased during physiologically elevated FFAs induced by LHI, which was accompanied by mild hyperinsulinemia. Interestingly, a mild elevation of FFAs resulting from complete insulin deficiency also increased FGF-21 levels. These results from two independent human RCTs suggest that FFAs increase circulating FGF-21, while insulin is only of minor importance under physiological conditions. This mechanism might explain the apparent paradox of increased FGF-21 levels in obesity, insulin resistance, and starvation.

A1C Is Associated With Intima-Media Thickness in Individuals With Normal Glucose Tolerance

OBJECTIVE One-hour glucose during an oral glucose tolerance test (OGTT) was recently proposed as a valuable marker to identify individuals with normal glucose tolerance (NGT) and increased intima-media thickness (IMT). However, central markers of glycemic control were not considered. The aim of this study was to identify which marker of glycemic control is most informative with respect to the variation of IMT in individuals with NGT. RESEARCH DESIGN AND METHODS Cardiovascular risk factors, glucose metabolism (OGTT), and IMT were determined in 1,219 nondiabetic individuals (851 women, 368 men; 558 with NGT). RESULTS One-hour glucose and A1C levels were significantly correlated to carotid IMT in individuals with NGT, whereas fasting and 2-h glucose levels were not informative. Only A1C was associated with IMT independent of other confounders, whereas 1-h glucose was not informative. Comparable results were found in the total cohort, including individuals with IFG and IGT. CONCLUSIONS A1C was the most informative glycemic marker with respect to IMT in individuals with NGT.

Intravenous Lipid and Heparin Infusion-Induced Elevation in Free Fatty Acids and Triglycerides Modifies Circulating Androgen Levels in Women: A Randomized, Controlled Trial

BACKGROUND The polycystic ovarian syndrome (PCOS) is characterized by hyperandrogenism and associated with obesity and impaired glucose metabolism. Despite the high prevalence of PCOS and the considerable clinical impact, the precise interplay between metabolism and hyperandrogenemia is not entirely clear. OBJECTIVE The objective of the study was to analyze the effects of iv lipid and heparin infusion on circulating androgen levels in healthy women. DESIGN This was a randomized, controlled, crossover trial. SETTING The study was conducted at an endocrinology center. PATIENTS Patients included 12 healthy young women during the early follicular phase of two subsequent cycles. INTERVENTION After an overnight fast, a 20% lipid/heparin or a saline/heparin infusion was administered in random order for 330 min. MAIN OUTCOME MEASURES A detailed characterization of androgen metabolism was performed. RESULTS Elevations in free fatty acids and triglycerides, induced by lipid/heparin infusion, elevates the levels of androstenedione, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), testosterone, 5alpha-dihydrotestosterone, estrone, and 17beta-estradiol. Urinary excretion of DHEA, DHEAS, 5-androstene-3beta,17beta-diol, and the sum of urinary excreted DHEA and its 16-hydroxylated downstream metabolites, 16alpha-hydroxy-DHEA and 5-androstene-3beta,16alpha,17beta-triol, were reduced. CONCLUSION The mechanism of iv lipid and heparin infusion-induced elevation of circulating androgens described here might contribute to the development of hyperandrogenism in women with PCOS and suggests that lowering of hyperlipidemia might be a potential therapeutic target in patients with PCOS to treat hyperandrogenemia.

Increased plasma retinol binding protein 4 levels in patients with inflammatory cardiomyopathy

Chronic heart failure (CHF) is associated with a higher risk for diabetes mellitus. Retinol binding protein 4 (RBP 4) is an adipose tissue‐derived protein with pro‐diabetogenic effects. A complete understanding of the association of CHF and insulin resistance remains elusive. The purpose of this study was to examine the relationship between CHF and diabetes mellitus.