Annett Hoffmann

Circulating Angiopoietin-like Protein 8 Is Independently Associated With Fasting Plasma Glucose and Type 2 Diabetes Mellitus

OBJECTIVE Angiopoietin-like protein 8 (Angptl8) has recently been introduced as a novel adipokine/hepatokine that promotes pancreatic β-cell proliferation and improves glucose tolerance in mouse models of insulin resistance. However, regulation of Angptl8 in human type 2 diabetes mellitus (T2DM) and renal dysfunction has not been determined. RESEARCH DESIGN AND METHODS Serum Angptl8 levels were quantified by ELISA in 62 patients with T2DM as compared with 58 nondiabetic subjects in vivo. Within both groups, about half of the patients were on chronic hemodialysis or had an estimated glomerular filtration rate above 50 mL/min/1.73 m(2). Furthermore, we investigated the effect of insulin and differentiation on Angptl8 mRNA expression in 3T3-L1 adipocytes in vitro. RESULTS Median [interquartile range] serum Angptl8 levels were higher in patients with T2DM (1.19 [0.37] μg/L) as compared with nondiabetic subjects (1.03 [0.47] μg/L) (P = .005). Furthermore, the adipokine/hepatokine was significantly higher in women (1.21 [0.47] μg/L) as compared with men (1.05 [0.44] μg/L]) (P = .013). In multivariate analysis, fasting glucose and T2DM but not renal function remained independent and positive predictors of circulating Angptl8 even after adjustment for markers of obesity, lipid status, and inflammation (P < .05). Furthermore, Angptl8 mRNA expression was induced by insulin and during adipogenesis in 3T3-L1 adipocytes in vitro. CONCLUSIONS Circulating Angptl8 is positively and independently associated with T2DM and fasting glucose in vivo. Furthermore, Angptl8 mRNA expression is induced by insulin and during adipogenesis in 3T3-L1 adipocytes in vitro.

Circulating adipocyte fatty acid-binding protein induces insulin resistance in mice in vivo

Circulating levels of the adipokine adipocyte fatty acid‐binding protein (AFABP) are increased in obesity. However, the influence of circulating AFABP on insulin sensitivity in vivo remains unclear.

Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin.

OBJECTIVES Conflicting evidence concerning leptin in atherosclerosis has been published. Furthermore, dose-dependent effects of leptin on atherogenesis have not been studied. METHODS Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR(-/-);ob/ob) mice were treated with saline, 0.1, 0.5, or 3.0mg/kg body weight (BW)/d recombinant leptin over 12weeks starting at 8weeks of age. Aortic root and brachiocephalic artery (BCA) atherosclerotic lesions were analyzed by oil red O staining. Furthermore, glucose homeostasis, lipid metabolism, and liver function including tissue studies were assessed in all animals. RESULTS Leptin treatment dose-dependently decreased BW in LDLR(-/-);ob/ob mice as compared to saline. Mice in the 0.1 and 0.5mg/kgBW/d groups remained heavier (i.e. subphysiological leptin dose) and in the 3.0mg/kgBW/d group had similar weight (i.e. physiological leptin dose) as compared to non-leptin-deficient LDLR(-/-) animals. Recombinant leptin dose-dependently reduced plaque area in the aortic root and the BCA by 36% and 58%, respectively. Leptin-mediated reductions of plasma total and LDL-cholesterol (Chol) remained independent predictors for aortic root plaque area. Chol content in liver, as well as hepatic expression of key lipid and proinflammatory genes, were dose-dependently regulated by leptin. Furthermore, leptin treatment increased circulating levels and adipose tissue mRNA expression of the adipokine adiponectin. CONCLUSIONS Leptin administration within the subphysiological to physiological range diminishes atherosclerotic lesions. Leptin appears to mediate its antiatherogenic effects indirectly through reduction of hypercholesterolemia and liver steatosis, as well as upregulation of insulin-sensitizing and atheroprotective adiponectin.

Regulation of the novel adipokines/ hepatokines fetuin A and fetuin B in gestational diabetes mellitus

OBJECTIVE Fetuin B has recently been introduced as a novel adipokine/hepatokine which is significantly increased in hepatic steatosis and mediates impaired insulin action, as well as glucose intolerance. However, regulation of fetuin B in gestational diabetes mellitus (GDM), as well as its longitudinal changes in the peripartum period, have not been elucidated, so far. DESIGN AND METHODS Circulating fetuin A and fetuin B were quantified in 74 women with GDM and 74 healthy and gestational age-matched controls by enzyme-linked immunosorbent assay during pregnancy (median gestational age: 201days). Furthermore, fetuin B was quantified during pregnancy as compared to postpartum levels in a follow-up study (median time after delivery: 4years and 115days). RESULTS Median [interquartile range] serum fetuin B levels were significantly higher in women with GDM (4.8 [1.7] mg/l) as compared to non-diabetic pregnant controls (4.3 [1.2] mg/l) (p=0.013) during pregnancy. In multivariate analysis, GDM status, insulin resistance, and fetuin A were independent and positive predictors of circulating fetuin B. Furthermore, fetuin B serum concentrations significantly decreased after delivery from 4.6 [1.7] mg/l (prepartum) to 3.0 [2.2] mg/l (postpartum) in all women (p<0.001). CONCLUSIONS Women with GDM have significantly higher fetuin B levels as compared to healthy pregnant control women and GDM status, insulin resistance, and fetuin A positively predict circulating fetuin B. Postpartum fetuin B is decreased as compared to prepartum values suggesting a placental co-secretion of this novel adipokine/hepatokine. Further studies need to elucidate factors contributing to fetuin B regulation in humans, as well as the pathophysiological significance of fetuin B upregulation in GDM.

Leptin Within the Subphysiological to Physiological Range Dose Dependently Improves Male Reproductive Function in an Obesity Mouse Model

Obesity has recently been linked with reduced fertility, and the mechanisms underpinning this effect are currently unknown. The adipokine leptin is dysregulated in obesity and affects reproductive tracts; therefore, we investigated the dose-dependent effects of leptin on Leydig cell function and spermatogenesis. Eight-week-old leptin-deficient obese (ob/ob) male mice were treated with subphysiological (0.1- or 0.5-mg/kg body weight [BW]/d) or physiological (3.0-mg/kg BW/d) doses of leptin or saline for 12 weeks (chronic treatment) or 72 hours (acute treatment). We then evaluated male reproductive function markers. Mean testis weight increased significantly in the 0.1- and 3.0-mg/kg BW/d groups compared with saline controls (both P < .05). Intratesticular testosterone levels relative to testis weight significantly increased in the 0.5-mg/kg BW/d group compared with saline controls (P < .05). FSH levels increased in a dose-dependent manner with leptin treatment, whereas LH levels did not change. Leptin treatment significantly up-regulated both mRNA and protein expression of the steroidogenic enzyme cytochrome P450 17A1. Spermatogenesis improved in leptin-treated animals. Significantly more seminiferous tubules were observed in stages I-VIII (P < .01), and there were fewer abnormal seminiferous tubule structures (P < .01). Acute treatment with physiological leptin doses partially improved male reproductive markers without changing BW. Administration of subphysiological to physiological doses of leptin improves Leydig cell function and spermatogenesis.

Serum concentrations of fibroblast growth factor 21 are elevated in patients with congenital or acquired lipodystrophy.

OBJECTIVE Patients with lipodystrophy (LD) suffer from loss of subcutaneous adipose tissue accompanied by dysregulation of several adipocyte-secreted factors. However, regulation of adipocyte-expressed fibroblast growth factor (FGF) 21 which acts in an insulin-mimetic, lipid-lowering, and anti-atherogenic manner has not been investigated in non-human immunodeficiency virus (HIV) LD. MATERIAL AND METHODS Circulating serum FGF21 levels were quantified in 37 patients with non-HIV LD and 37 controls matched for age, gender, and body mass index. Moreover, FGF21 plasma levels and mRNA expression were measured in LD mice and control animals. Additionally, serum FGF21 levels were assessed in 10 LD patients before and during metreleptin therapy. RESULTS Median FGF21 serum concentrations were significantly higher in LD patients (381.2ng/l) as compared to the control group (231.2ng/l; p=0.023). There was an independent and positive association between circulating FGF21 and serum triglycerides (TG), as well as fibrate treatment, in multiple linear regression analysis. LD mice showed significantly upregulated FGF21 plasma levels (4.5-fold), as well as mRNA expression in various adipose tissue depots and liver as compared to controls (p<0.05). Metreleptin treatment did not significantly alter circulating FGF21 levels in human subjects. CONCLUSIONS Serum concentrations of FGF21 are elevated in patients with non-HIV LD with adipose tissue and liver being potential sources of increased production. TG and fibrate treatment are independent positive predictors of circulating FGF21.

Circulating serum chemerin levels are elevated in lipodystrophy.

Lipodystrophy (LD) is characterized by loss of adipose tissue, dysregulation of adipokines and severe metabolic complications. Regulation of the insulin resistance‐inducing and proinflammatory adipokine chemerin has not been assessed in LD. Therefore, we determined chemerin serum levels in LD, chemerin mRNA expression in insulin‐sensitive tissues of LD mice, as well as the impact of metreleptin treatment on circulating chemerin in LD patients.

Progranulin is increased in human and murine lipodystrophy

AIMS Lipodystrophies (LD) are genetic or acquired disorders sharing the symptom of partial or complete adipose tissue deficiency and a dysregulation of adipokines including leptin and adiponectin. Progranulin, an adipokine with proinflammatory and insulin resistance-inducing characteristics, has not been investigated in LD so far. METHODS Circulating progranulin was determined in LD patients (N=37) and in age-, gender-, and body mass index-matched healthy control subjects (N=37). Additionally, we investigated progranulin expression in an LD mouse model as compared to wild-type mice. Moreover, we elucidated circulating progranulin before and during metreleptin supplementation in 10 patients with LD. RESULTS Median [interquartile range] circulating progranulin was increased in patients with LD (82.9 [25.9] μg/l) as compared to controls (73.6 [22.8] μg/l) (p=0.005). C-reactive protein (CRP) remained an independent and positive predictor of progranulin in multivariate analysis. Progranulin mRNA was significantly upregulated in all adipose tissue depots, i.e. visceral, subcutaneous, and brown adipose tissue, and in muscle of LD animals versus wild-type mice. Progranulin levels did not significantly change during metreleptin supplementation. CONCLUSIONS Progranulin serum concentration is increased in patients with LD, and shows an independent and positive correlation with CRP. Different adipose tissue depots and muscle might be potential origins of elevated progranulin.

The novel adipokine/hepatokine fetuin B in severe human and murine diabetic kidney disease

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since jeudi 16 fevrier 2017

FSTL3 is increased in renal dysfunction

Background Follistatin-like 3 (FSTL3) is a novel cytokine that regulates insulin sensitivity and counteracts activin/myostatin signalling. In the present study, regulation of FSTL3 in renal dysfunction was investigated in both human chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Furthermore, mFSTL3 expression was analysed in insulin-sensitive tissues in a mouse model of CKD. Methods Circulating FSTL3 was quantified by enzyme-linked immunosorbent assay in 581 patients with CKD covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5. Furthermore, FSTL3 was measured in 61 patients before and within 30 h after elective unilateral nephrectomy, an established model of AKD. Moreover, mFSTL3 mRNA expression was investigated in an animal CKD model, that is, eNOS-/-db/db mice, and compared with littermate controls. Results Median circulating FSTL3 levels significantly and continuously increased with deteriorating renal function (eGFR category G1: 6.1; G2: 8.2; G3: 12.7; G4: 18.5; G5: 32.1 µg/L; P < 0.001). In both human CKD and AKD, renal dysfunction remained the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. FSTL3 was independently associated with an adverse cardiometabolic profile. In CKD mice, hepatic mFSTL3 mRNA expression was increased more than 6-fold as compared with controls. Conclusions Circulating FSTL3 is significantly and independently associated with renal function in both patients with CKD and AKD. Hepatic mFSTL3 mRNA upregulation might contribute to increased FSTL3 levels in CKD. Our results are in agreement with the hypothesis that FSTL3 is eliminated by the kidneys and might counteract adverse activin/myostatin signalling observed in renal dysfunction.