Sebastian Weise

Interleukin-1ß induces the novel adipokine chemerin in adipocytes in vitro

Chemerin has recently been characterized as a novel adipokine playing a crucial role in adipocyte differentiation and insulin signalling. In the current study, the impact of insulin resistance-inducing and proinflammatory interleukin (IL)-1beta on chemerin protein secretion and mRNA expression was determined in 3T3-L1 adipocytes. Interestingly, IL-1beta significantly induced chemerin protein secretion almost 1.3-fold from 5.89 ng/ml (basal) to 7.52 ng/ml. Furthermore, chemerin mRNA synthesis was significantly stimulated by IL-1beta in a dose-dependent fashion with 1.5-fold induction seen at IL-1beta concentrations as low as 0.07 ng/ml and maximal 2.6-fold upregulation found at 2 ng/ml effector. Induction of chemerin mRNA by IL-1beta was time-dependent in both 3T3-L1 adipocytes and brown fat cells. Signalling studies suggested that Janus kinase 2, nuclear factor kappa B, p44/42 mitogen-activated protein kinase, and phosphatidylinositol 3-kinase are involved in IL-1beta-induced chemerin mRNA expression. Furthermore, recombinant chemerin downregulated insulin-stimulated glucose uptake. Taken together, we show that chemerin is upregulated in fat cells by IL-1beta and might modulate the effects of IL-1beta on adipocyte metabolism and insulin sensitivity.

Evidence of Early Alterations in Adipose Tissue Biology and Function and Its Association With Obesity-Related Inflammation and Insulin Resistance in Children

Accumulation of fat mass in obesity may result from hypertrophy and/or hyperplasia and is frequently associated with adipose tissue (AT) dysfunction in adults. Here we assessed early alterations in AT biology and function by comprehensive experimental and clinical characterization of 171 AT samples from lean and obese children aged 0 to 18 years. We show an increase in adipocyte size and number in obese compared with lean children beginning in early childhood. These alterations in AT composition in obese children were accompanied by decreased basal lipolytic activity and significantly enhanced stromal vascular cell proliferation in vitro, potentially underlying the hypertrophy and hyperplasia seen in obese children, respectively. Furthermore, macrophage infiltration, including the formation of crown-like structures, was increased in AT of obese children from 6 years on and was associated with higher hs-CRP serum levels. Clinically, adipocyte hypertrophy was not only associated with leptin serum levels but was highly and independently correlated with HOMA-IR as a marker of insulin resistance in children. In summary, we show that adipocyte hypertrophy is linked to increased inflammation in AT in obese children, thereby providing evidence that obesity-associated AT dysfunction develops in early childhood and is related to insulin resistance.

Lipocalin‐2 is induced by interleukin‐1β in murine adipocytes in vitro

Lipocalin‐2 (Lcn2) has recently been isolated as an adipocyte‐secreted acute phase reactant that plays a role in insulin resistance, obesity, and atherosclerotic disease. In the current study, we determined regulation of Lcn2 by the proinflammatory and insulin resistance‐inducing cytokine interleukin (IL)‐1β in 3T3‐L1 and brown adipocytes by relative real‐time reverse transcription‐polymerase chain reaction. Interestingly, IL‐1β dramatically induced Lcn2 mRNA in both adipocyte models. Furthermore, Lcn2 protein secretion was dramatically upregulated in 3T3‐L1 adipocytes after 24 h of IL‐1β treatment. Experiments using pharmacological inhibitors indicated that IL‐1β‐induced Lcn2 expression is mediated via nuclear factor κB and janus kinase 2. Taken together, our results show an upregulation of Lcn2 by IL‐1β in fat cells implicating a potential role of this adipocyte‐secreted acute phase reactant in the development of insulin resistance, obesity, and associated disorders including cardiovascular disease. J. Cell. Biochem. 106: 103–108, 2009.

Interleukin-1ß is a positive regulator of TIARP/STAMP2 gene and protein expression in adipocytes in vitro

The impact of interleukin (IL)‐1ß on tumor necrosis factor α‐induced adipose‐related protein (TIARP)/six‐transmembrane protein of prostate 2 (STAMP2) was determined in adipocytes. TIARP/STAMP2 mRNA synthesis was significantly stimulated by IL‐1ß in a dose‐ and time‐dependent fashion in 3T3‐L1 adipocytes. Signaling studies suggested that janus kinase 2, nuclear factor κB, and p44/42 mitogen‐activated protein kinase are involved in IL‐1ß‐induced TIARP/STAMP2 mRNA expression. Furthermore, IL‐1ß, TNFα, and IL‐6 showed synergistic stimulatory effects on TIARP/STAMP2 gene expression. Moreover, both TIARP/STAMP2 mRNA synthesis and protein expression were induced by IL‐1ß in fully differentiated human mesenchymal stem cell‐derived adipocytes (hMSC‐Ad). Taken together, TIARP/STAMP2 is highly upregulated in 3T3‐L1 cells and hMSC‐Ad by IL‐1ß and might, therefore, modulate proinflammatory and insulin resistance‐inducing effects of IL‐1ß.

The adipokine SAA3 is induced by interleukin-1β in mouse adipocytes

Serum amyloid A (SAA) 3 has been characterized as an inflammatory adipocyte‐secreted acute‐phase reactant. In the current study, regulation of SAA3 by the proinflammatory and insulin resistance‐inducing cytokine interleukin (IL)‐1β was determined in 3T3‐L1 and brown adipocytes. Interestingly, SAA3 mRNA and protein synthesis were dramatically increased by IL‐1β in a time‐dependent fashion with maximal induction after 24 h. Furthermore, IL‐1β significantly induced SAA3 mRNA expression dose‐dependently with maximal 36.4‐fold upregulation seen at 2 ng/ml effector. Moreover, IL‐1β‐induced SAA3 expression was mediated by nuclear factor‐κB and janus kinase 2. Taken together, our data show a potent upregulation of SAA3 by IL‐1β. J. Cell. Biochem. 104: 2241–2247, 2008.

Health impact in children and adolescents

Obesity in children and adolescents is associated with multiple comorbidities, including metabolic, cardiovascular, gastrointestinal, pulmonary, orthopedic and psychological disorders. In fact, cardiovascular and metabolic impairments in childhood and adolescence constitute major risk factors for developing cardiovascular disease in adulthood. Thus, obesity in childhood and adolescence leads to a higher morbidity and mortality in adulthood. Therefore, strong emphasis must be laid on the prevention and therapy of childhood obesity. Treatment requires a multidisciplinary and multiphase approach including dietary management, physical activity, pharmacotherapy and bariatric surgery. This paper reviews the different comorbidities of childhood obesity supporting the notion of a multidisciplinary therapy concept.

Amyloid Precursor Protein Expression Is induced by Tumor Necrosis Factor α in 3T3-L1 Adipocytes

Amyloid precursor protein (APP) has been characterized as an adipocyte‐secreted protein that might contribute to obesity‐related insulin resistance, inflammation, and dementia. In the current study, regulation of APP by the proinflammatory and insulin resistance‐inducing cytokine tumor necrosis factor (TNF) α was determined in 3T3‐L1 adipocytes. Interestingly, APP protein synthesis and mRNA expression were significantly increased by TNFα in a time‐dependent manner with maximal induction observed after 24 h of treatment. Furthermore, TNFα induced APP mRNA expression dose‐dependently with maximal 6.4‐fold upregulation seen at 100 ng/ml effector. Moreover, inhibitor experiments suggested that TNFα‐induced APP expression was mediated by nuclear factor κ B. Taken together, we show for the first time a potent upregulation of APP by TNFα suggesting a potential role of this adipocyte‐secreted protein in TNFα‐induced insulin resistance and inflammatory disease. J. Cell. Biochem. 108: 1418–1422, 2009.

Tissue inhibitor of metalloproteinase-1 mRNA production and protein secretion are induced by interleukin-1β in 3T3-L1 adipocytes

The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1 beta on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1 beta. Thus, IL-1 beta induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1 beta relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1 beta in a dose-dependent fashion with 2.5-fold induction seen at IL-1 beta concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1 beta treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1 beta-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1 beta, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.

Genetic Contribution of Variants near SORT1 and APOE on LDL Cholesterol Independent of Obesity in Children

Objective To assess potential effects of variants in six lipid modulating genes (SORT1, HMGCR, MLXIPL, FADS2, APOE and MAFB) on early development of dyslipidemia independent of the degree of obesity in children, we investigated their association with total (TC), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) cholesterol and triglyceride (TG) levels in 594 children. Furthermore, we evaluated the expression profile of the candidate genes during human adipocyte differentiation. Results Expression of selected genes increased 101 to >104 fold during human adipocyte differentiation, suggesting a potential link with adipogenesis. In genetic association studies adjusted for age, BMI SDS and sex, we identified significant associations for rs599839 near SORT1 with TC and LDL-C and for rs4420638 near APOE with TC and LDL-C. We performed Bayesian modelling of the combined lipid phenotype of HDL-C, LDL-C and TG to identify potentially causal polygenic effects on this multi-dimensional phenotype and considering obesity, age and sex as a-priori modulating factors. This analysis confirmed that rs599839 and rs4420638 affect LDL-C. Conclusion We show that lipid modulating genes are dynamically regulated during adipogenesis and that variants near SORT1 and APOE influence lipid levels independent of obesity in children. Bayesian modelling suggests causal effects of these variants.