Leptin treatment has vasculo-protective effects in lipodystrophic mice.

Lipodystrophy syndromes (LDs) are characterized by loss of adipose tissue, metabolic complications such as dyslipidemia, insulin resistance, and fatty liver disease, as well as accelerated atherosclerosis. As a result of adipose tissue deficiency, the systemic concentration of the adipokine leptin is reduced. A current promising therapeutic option for patients with LD is treatment with recombinant leptin (metreleptin), resulting in reduced risk of mortality. Here, we investigate the effects of leptin on endothelial to mesenchymal transition (EndMT), which impair the functional properties of endothelial cells and promotes atherogenesis in LD. Leptin treatment reduced inflammation and TGF-ß2-induced expression of mesenchymal genes and prevented impairment of endothelial barrier function. Treatment of lipodystrophic- and atherosclerosis-prone animals (Ldlr-/-; aP2-nSrebp1c-Tg) with leptin reduced macrophage accumulation in atherosclerotic lesions, vascular plaque protrusion, and the number of endothelial cells with mesenchymal gene expression, confirming a reduction in EndMT in LD after leptin treatment. Treatment with leptin inhibited LD-mediated induction of the proatherosclerotic cytokine growth/differentiation factor 15 (GDF15). Inhibition of GDF15 reduced EndMT induction triggered by plasma from patients with LD. Our study reveals that in addition to the effects on adipose tissue function, leptin treatment exerts beneficial effects protecting endothelial function and identity in LD by reducing GDF15.

Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor ß superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

Serum concentrations of fetuin B in lipodystrophic patients.

OBJECTIVE: Fetuin B is an adipokine/hepatokine which is significantly elevated in insulin resistance/type 2 diabetes mellitus and hepatic steatosis. Regulation of fetuin B in patients with lipodystrophy (LD) - a disease group which is characterized by subcutaneous adipose tissue loss, hypertriglyceridemia, hepatic steatosis, insulin resistance, and dysregulation of several adipokines - has not been elucidated so far. MATERIAL AND METHODS: Serum fetuin B levels were determined in 37 patients with LD, as well as in a control cohort consisting of 37 non-LD participants matched for age, gender, and body mass index. Furthermore, fetuin B was correlated with parameters of lipid metabolism, glucose control, renal function, and inflammation. RESULTS: Median fetuin B serum levels were not significantly different between patients with LD (2980.7 µg/l; interquartile range: 841.7 µg/l) and non-LD controls (2647.3 µg/l; interquartile range: 923.6 µg/l; p = .105). Fetuin B was associated with age, body mass index, markers of renal function, and C reactive protein (CRP) in univariate correlation analyses. The associations with age and creatinine remained significant in multiple linear regression analysis. CONCLUSIONS: Fetuin B serum concentrations are not significantly different between patients with LD and non-LD controls. Fetuin B does not seem to be a major pathogenetic factor in LD.

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.

Adipocyte and epidermal fatty acid-binding protein serum concentrations in patients with lipodystrophy.

OBJECTIVE: Lipodystrophy (LD) syndromes are associated with diabetes mellitus, hypertriglyceridemia, and coronary artery disease. One pathogenetic factor of LD is dysregulation of several adipokines. However, the insulin resistance- and dyslipidemia-promoting adipokines adipocyte (AFABP) and epidermal (EFABP) fatty acid-binding protein have not been investigated in non-HIV-associated LD so far. MATERIAL AND METHODS: We performed a cross-sectional analysis of AFABP and EFABP serum concentrations in 37 LD patients and 37 age-, gender-, and body mass index-matched healthy controls. Moreover, AFABP and EFABP were correlated to clinical and biochemical parameters of inflammation, glucose control, and lipid metabolism. RESULTS: There was no significant difference in median circulating AFABP and EFABP levels between LD patients (21.7µg/l and 7.5µg/l, respectively) and healthy controls (24.5µg/l and 8.6µg/l, respectively). Neither AFABP nor EFABP were related to markers of impaired glucose control or lipid metabolism. Multiple linear regression analysis showed a positive and independent association of AFABP with gender, serum leptin levels, and body mass index. CONCLUSIONS: Circulating levels of AFABP and EFABP are not decreased in LD despite adipose tissue loss in contrast to other adipokines including leptin and adiponectin.

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.

Circulating serum chemerin levels are elevated in lipodystrophy.

OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: Serum chemerin, as well as clinical and biochemical parameters of glucose metabolism, lipid metabolism, and inflammation, was measured in 37 LD patients and 37 age-, gender- and body mass index-matched controls. Furthermore, chemerin mRNA expression was determined in LD mice and controls. Moreover, circulating chemerin was assessed at five different time points in 10 LD patients treated with metreleptin over 1 year. RESULTS: Median serum chemerin levels were significantly higher in 37 subjects with LD (234·3 µg/l) as compared to controls (204·0 µg/l) (P = 0·002). Multiple linear regression analysis showed that circulating chemerin was independently and positively associated with glycosylated haemoglobin A1c (HbA1c) and C-reactive protein (CRP). Chemerin mRNA expression was significantly increased 2·5-fold in visceral adipose tissue (VAT) and 5·3-fold in brown adipose tissue (BAT) of LD mice as compared to controls (P < 0·01). Circulating chemerin was not significantly altered by metreleptin treatment. CONCLUSIONS: Circulating levels of the adipokine chemerin are elevated in LD, as well as independently and positively associated with HbA1c and CRP. Increased chemerin might originate from VAT and BAT.

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.

Serum levels of the adipokine Pref-1 in gestational diabetes mellitus.

OBJECTIVE: Pref-1 has recently been introduced as a novel insulin resistance-inducing adipokine influencing adipogenesis. The role of circulating Pref-1 in patients with gestational diabetes mellitus (GDM) has not been assessed so far. METHODS: We determined circulating Pref-1 serum levels in 74 patients with GDM, as well as 74 healthy age-, body mass index (BMI-), and gestational age-matched pregnant controls. Furthermore, Pref-1 was correlated with anthropometric measures, as well as biochemical markers, of glucose homeostasis, lipid metabolism, renal function, and inflammation. RESULTS: Mean serum Pref-1 levels during pregnancy were not significantly different between patients with GDM (0.40µg/l) and healthy controls (0.42µg/l) (p=0.655). Multivariate analysis revealed that gestational age at blood sampling, triglycerides (TG), and creatinine independently and positively predicted Pref-1 levels (p<0.05). Furthermore, Pref-1 levels were independently and negatively associated with BMI and C reactive protein (p<0.05). CONCLUSIONS: Pref-1 is probably not a major contributor to GDM pathophysiology but might directly contribute to TG metabolism, as well as depend on gestational age and renal function.

The adipokine preadipocyte factor-1 is downregulated in preeclampsia and expressed in placenta.

BACKGROUND: Adipokines contribute to the development of preeclampsia (PE), a severe pregnancy complication which increases the future risk for cardiovascular and metabolic disease in both mother and newborn. Pre-adipocyte factor-1 (Pref-1) was recently introduced as a novel antiangiogenic and antiadipogenic adipokine. MATERIAL AND METHODS: Pref-1 was quantified in patients with PE (n=51) and healthy pregnant controls (n=51) during pregnancy, as well as 6 months after delivery (study population 1). Furthermore, Pref-1 was investigated in the immediate peripartal period and the placenta in 40 healthy pregnant women undergoing elective cesarean section (study population 2). RESULTS: In study population 1, median Pref-1 serum concentrations during pregnancy were significantly lower in women with PE (0.5 µg/l) as compared to healthy pregnant controls (0.7 µg/l) (p<0.001). Furthermore, Pref-1 serum concentrations were independently predicted by PE, leptin levels, and gestational age in this population. In both study populations, Pref-1 serum levels significantly decreased after delivery as compared to prepartal levels. Moreover, significant expression of Pref-1 was detected in placental tissue. CONCLUSION: Maternal Pref-1 serum concentrations are significantly decreased in PE. The pathophysiological significance of this regulation needs to be studied in more detail in future experiments.

Serum levels of sclerostin in cardiometabolic disorders during pregnancy.

OBJECTIVE: Sclerostin has recently been introduced as a novel osteocyte-secreted factor which is associated with an adverse metabolic profile. However, regulation of circulating sclerostin in cardiometabolic disorders during pregnancy including gestational diabetes mellitus (GDM) and preeclampsia (PE) has not been comprehensively assessed, so far. METHODS: Serum levels of sclerostin were quantified in 72 women with GDM and in 72 healthy, pregnant, gestational age-matched controls (study population 1). Furthermore, circulating sclerostin was assessed in 51 women with PE as compared to 51 pregnant controls in a second cohort (study population 2). RESULTS: In the first study population (GDM), median [interquartile range] sclerostin levels were not significantly different in women with GDM as compared to controls (GDM: 19.2 [8.1]pmol/l; controls: 18.6 [7.1]pmol/l; p=0.906). Interestingly, C reactive protein was a negative and independent predictor of circulating sclerostin in the GDM cohort in multivariate analysis. In study population 2 (PE), serum levels of sclerostin were not different between women with PE and controls (PE: 18.8 [9.2]pmol/l; controls: 19.3 [8.8]pmol/l; p=0.504). Furthermore, the osteocyte-secreted factor was not related to any metabolic and gestational parameter in this cohort. CONCLUSIONS: Sclerostin serum levels are not associated with an adverse metabolic profile during pregnancy in women with GDM and PE. The physiological significance of different associations of circulating sclerostin between pregnancy and non-pregnant status needs to be determined in future experiments.

Global DNA methylation levels in human adipose tissue are related to fat distribution and glucose homeostasis.

AIMS/HYPOTHESIS: Epigenetic alterations may influence the metabolic pathways involved in human obesity. We hypothesised that global DNA methylation levels in adipose tissue might be associated with obesity and related phenotypes. METHODS: We measured global DNA methylation levels in paired samples of subcutaneous adipose tissue (SAT) and omental visceral adipose tissue (OVAT) from 51 individuals, and in leucocytes from 559 Sorbs, a population from Germany, using LUminometric Methylation Assay (LUMA). To further investigate the underlying mechanisms of the observed associations, we measured global methylation levels in 3T3-L1 adipocytes exposed to glucose, insulin and lipids. RESULTS: Global methylation levels (±SD) were significantly higher in OVAT (74.27% ± 2.2%) compared with SAT (71.97% ± 2.4%; paired t test, p < 1 × 10(-9)). Furthermore, global methylation levels in SAT were positive correlates of measures of fat distribution (waist measurement, WHR) and glucose homeostasis (HbA1c) (all p < 0.015 after accounting for multiple testing and covariates). Global methylation levels in the German Sorb cohort were associated with glucose homeostasis, but this association did not withstand adjustment for covariates. Exposure of 3T3-L1 adipocytes to insulin, palmitate and glucose decreased global methylation levels 1 h after treatment relative to controls. CONCLUSIONS/INTERPRETATION: Our data suggest that the variability in global methylation in adipose tissue might be related to alterations in glucose metabolism.

Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction.

OBJECTIVE: Fibroblast growth factor (FGF)-21 has recently been introduced as a circulating adipokine which reverses insulin resistance and obesity in rodents. In this study, regulation of FGF-21 in renal dysfunction was elucidated in both chronic kidney disease (CKD) and acute kidney dysfunction (AKD). STUDY DESIGN AND METHODS: Serum concentrations of total FGF-21 were quantified by enzyme-linked immunosorbent assay in 499 patients with CKD stages 1-5 (study population 1). Furthermore, total FGF-21 was determined before and within 30 h after unilateral nephrectomy, a model of AKD, in 32 patients (study population 2). FGF-21 levels were correlated to anthropometric and biochemical parameters of renal function, glucose and lipid metabolism, as well as inflammation, in both studies. RESULTS: In study population 1, median [interquartile range] circulating FGF-21 adjusted for age, gender and body mass index was significantly different between CKD stages with highest values detectable in stage 5 (stage 1: 86·4 [132·9]; 2: 206·4 [223·1]; 3: 289·8 [409·3]; 4: 591·3 [789·0]; 5: 1918·1 [4157·0] ng/l). Furthermore, estimated glomerular filtration rate remained a strong independent and negative predictor of FGF-21. In study population 2, FGF-21 increased significantly postsurgically (325·0 [984·0] ng/l) as compared to presurgical values (255·5 [243·0] ng/l). Furthermore, relative changes of FGF-21 were independently and positively predicted by relative changes of creatinine. CONCLUSIONS: We demonstrate that circulating FGF-21 is increased in both CKD and AKD. Our results suggest renal excretion as a major route for FGF-21 elimination. The pathophysiological significance of these findings needs to be elucidated in more detail.

Serum levels of irisin in gestational diabetes mellitus during pregnancy and after delivery.

OBJECTIVE: Irisin has recently been introduced as a novel an exercise-inducible myokine which improves glucose metabolism in mice. However, regulation of circulating irisin in gestational diabetes mellitus (GDM) and in the peripartal period has not been assessed so far. METHODS: Circulating irisin was quantified in 74 GDM patients and in 74 healthy, pregnant, gestational age-matched controls. In a subset of these patients (44 GDM, 41 controls), postpartum follow-up data were also available. In a second study population of 40 healthy women with singleton pregnancies undergoing elective Cesarean section, irisin was assessed in maternal serum before and within 24h after delivery, as well as in umbilical cord blood and in placental tissue. RESULTS: In the first study population, median [interquartile range] irisin levels were significantly higher in GDM patients as compared to controls after delivery (previous GDM: 446.3 [146.9]µg/l; controls: 378.0 [111.4]µg/l) but not during pregnancy (GDM: 482.1 [132.1]µg/l; controls: 466.6 [178.0]µg/l). Interestingly, fasting insulin (FI) was independently and positively associated with serum irisin in multivariate analysis during pregnancy. In agreement with these findings, relative changes (ratio) of FI independently and positively predicted relative changes of irisin (ratio) in the second study population. CONCLUSIONS: The myokine irisin is independently associated with FI in pregnancy. The physiological significance of these findings needs to be assessed in future experiments.

Serum levels of the adipokine fibroblast growth factor-21 are increased in preeclampsia.

BACKGROUND: Preeclampsia (PE) is a serious cardiovascular complication in pregnancy, which is associated with an increased future metabolic and cardiovascular risk for mother and newborn. Fibroblast growth factor (FGF)-21 was recently introduced as a novel adipokine improving glucose metabolism in vitro and in vivo. MATERIAL AND METHODS: We investigated serum FGF-21 levels in patients with PE (n=51) as compared to healthy, age-matched controls (n=51) during and 6 months after pregnancy. Furthermore, association of FGF-21 with markers of renal function, glucose and lipid metabolism, as well as inflammation, was elucidated in all individuals. RESULTS: Median maternal FGF-21 serum concentrations adjusted for body mass index and gestational age at blood sampling were significantly, almost 3-fold increased in PE patients (309.6 ng/l) as compared to healthy, age-matched pregnant women (105.2 ng/l) (p<0.001). Furthermore, FGF-21 concentrations were independently and positively correlated with triglycerides whereas an independent and negative association was observed with glomerular filtration rate and low density lipoprotein (LDL) cholesterol in pregnant women. Moreover, FGF-21 serum levels significantly decreased in former PE patients 6 months after pregnancy approaching levels found in control patients. CONCLUSIONS: Maternal FGF-21 serum concentrations are significantly increased in PE during pregnancy. Furthermore, triglycerides, glomerular filtration rate, and LDL cholesterol are independent predictors of circulating FGF-21 in pregnant women.

Renal function is a major predictor of circulating acyl-CoA-binding protein/diazepam-binding inhibitor.

Objective: Acyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far. Design/methods: Serum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate. Results: Median [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized ß=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mACBP mRNA expression in different tissues of CKD mice in vivo or in indoxyl sulfate-treated adipocytes in vitro. Conclusions: Circulating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.

Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass.

Intra-abdominal fat is associated with insulin resistance and cardiovascular risk. Levels of serum retinol-binding protein (RBP4), secreted by fat and liver cells, are increased in obesity and type 2 diabetes (T2D). Here we report that, in 196 subjects, RBP4 is preferentially expressed in visceral (Vis) versus subcutaneous (SC) fat. Vis fat RBP4 mRNA was increased approximately 60-fold and 12-fold in Vis and SC obese subjects respectively versus lean subjects, and approximately 2-fold with impaired glucose tolerance/T2D subjects versus normoglycemic subjects. In obese subjects, serum RBP4 was increased 2- to 3-fold, and serum transthyretin, which stabilizes RBP4 in the circulation, was increased 35%. Serum RBP4 correlated positively with adipose RBP4 mRNA and intra-abdominal fat mass and inversely with insulin sensitivity, independently of age, gender, and body mass index. RBP4 mRNA correlated inversely with GLUT4 mRNA in Vis fat and positively with adipocyte size in both depots. RBP4 levels are therefore linked to Vis adiposity, and Vis fat may be a major source of RBP4 in insulin-resistant states.

Fibroblast growth factor 21: effects on carbohydrate and lipid metabolism in health and disease.

PURPOSE OF REVIEW: The review summarizes recent findings examining the effects of fibroblast growth factor (FGF) 21 on carbohydrate and lipid metabolism with emphasis on publications from 2010. RECENT FINDINGS: FGF21 is considered to be a metabolic hormone rather than a traditional growth factor. Recent studies identified the important role of FGF21 in regulation of energy balance. Thus, the protein regulates hepatic metabolism and improves insulin sensitivity. Furthermore, central FGF21 action in the brain increases energy expenditure and insulin sensitivity in rodents. Interestingly, FGF21 expression is elevated in the adaptive response to fasting but also regulated by feeding-induced mechanisms. Moreover, FGF21 levels are elevated in obese animals and positively correlate with BMI in humans suggesting obesity as a FGF21-resistant state. SUMMARY: FGF21 is a metabolic hormone that is regulated by nutritional status and influences glucose and lipid metabolism by central and peripheral mechanisms. Future research is needed to expand our understanding of the diagnostic and therapeutic relevance of FGF21-dependent pathways in humans.

The Effect of FGF21 and Its Genetic Variants on Food and Drug Cravings, Adipokines and Metabolic Traits.

Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).

Leptin Improves Parameters of Brown Adipose Tissue Thermogenesis in Lipodystrophic Mice.

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.