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1.
Diabetes ; 52(12): 2914-22, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14633851

ABSTRACT

It is well recognized that the agouti/melanocortin system is an important regulator of body weight homeostasis. Given that agouti is expressed in human adipose tissue and that the ectopic expression of agouti in adipose tissue results in moderately obese mice, the link between agouti expression in human adipose tissue and obesity/type 2 diabetes was investigated. Although there was no apparent relationship between agouti mRNA levels and BMI, agouti mRNA levels were significantly elevated in subjects with type 2 diabetes. The regulation of agouti in cultured human adipocytes revealed that insulin did not regulate agouti mRNA, whereas dexamethasone treatment potently increased the levels of agouti mRNA. Experiments with cultured human preadipocytes and with cells obtained from transgenic mice that overexpress agouti demonstrated that melanocortin receptor (MCR) signaling in adipose tissue can regulate both preadipocyte proliferation and differentiation. Taken together, these results reveal that agouti can regulate adipogenesis at several levels and suggest that there are functional consequences of elevated agouti levels in human adipose tissue. The influence of MCR signaling on adipogenesis combined with the well-established role of MCR signaling in the hypothalamus suggest that adipogenesis is coordinately regulated with food intake and energy expenditure.


Subject(s)
Adipose Tissue/metabolism , Diabetes Mellitus, Type 2/physiopathology , Intercellular Signaling Peptides and Proteins/metabolism , 3T3 Cells , Adipocytes/cytology , Adipocytes/metabolism , Adipose Tissue/pathology , Adult , Agouti Signaling Protein , Animals , Cell Differentiation , Cell Division , Cells, Cultured , Dexamethasone/pharmacology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Female , Glucocorticoids/pharmacology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Male , Mesoderm/cytology , Mice , Middle Aged , RNA, Messenger/metabolism , Receptor, Melanocortin, Type 2/metabolism , Receptors, Corticotropin/metabolism , Receptors, Melanocortin , Signal Transduction , Stem Cells/metabolism
2.
Diabetes ; 52(7): 1611-8, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12829623

ABSTRACT

Insulin resistance is a component of type 2 diabetes and often precedes pancreatic beta-cell failure. Contributing factors include obesity and a central pattern of fat accumulation with a strong genetic component. The adipocyte secreted hormone resistin has been proposed as a link between the adipocyte and insulin resistance by inhibition of insulin-stimulated glucose uptake and/or blocking adipocyte differentiation. Here we report that the G/G genotype of a single nucleotide polymorphism (SNP) in the promoter of the human resistin gene, -180C>G, had significantly increased basal promoter activity in adipocytes. These data were recapitulated in vivo, where G/G homozygotes had significantly higher resistin mRNA levels in human abdominal subcutaneous fat. A significant interaction was also found between the -180C>G SNP, a marker of oxidative stress (NAD[P]H quinone oxidoreductase mRNA) and homeostasis model assessment of insulin resistance. In addition, resistin mRNA was positively and independently correlated with insulin resistance and hepatic fat as measured by liver X-ray attenuation. These data implicate resistin in the pathophysiology of the human insulin resistance syndrome, an effect mediated by the -180C>G promoter SNP and potentially cellular oxidative stress.


Subject(s)
Hormones, Ectopic/genetics , Insulin Resistance/genetics , Intercellular Signaling Peptides and Proteins , Oxidative Stress/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , Adipose Tissue/anatomy & histology , Adipose Tissue/physiology , Base Sequence , DNA Primers , Female , Gene Frequency , Genetic Markers , Genotype , Humans , Male , Models, Biological , NAD(P)H Dehydrogenase (Quinone)/genetics , Obesity/genetics , RNA, Messenger/genetics , Resistin
3.
Obes Res ; 11(1): 65-74, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12529487

ABSTRACT

OBJECTIVE: To validate the human mesenchymal stem cells (hMSCs) as a new in vitro model for the study of human adipogenesis, to develop the optimal protocol for the differentiation of hMSCs into adipocytes, and to describe effect of mitogen-activated protein kinase on hMSC differentiation into adipocytes. RESEARCH METHODS AND PROCEDURES: hMSCs, obtained commercially, were differentiated by exposure to insulin, dexamethasone, indomethacin, and 3-isobutyl-1-methylxanthine three times for 3 days each. Various differentiation conditions were examined to optimize differentiation as measured by Oil Red O staining. The gene expression during adipogenic conversion was assessed by reverse-transcription polymerase chain reaction, real-time reverse-transcription polymerase chain reaction, and Western blotting. RESULTS: hMSCs differentiated into adipocytes to a different extent depending on the experimental conditions. We have found that differentiation medium based on medium 199 and containing 170 nM insulin, 0.5 mM 3-isobutyl-1-methylxanthine, 0.2 mM indomethacin, 1 microM dexamethasone, and 5% fetal bovine serum was optimal. However, the replacement of fetal bovine serum with rabbit serum (15%) led to further enhancement of differentiation. Inhibition of mitogen-activated protein kinase activation also facilitated adipogenic conversion of hMSCs. The pattern of genes expressed during hMSC differentiation into adipocytes (adipsin, peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein-beta, GLUT4, and leptin) was similar to that observed in other in vitro adipocyte models. DISCUSSION: hMSCs are renewable sources of noncommitted precursors that are able to differentiate into mature adipocytes under the proper hormonal and pharmacological stimuli. Thus, hMSCs represent a new model for the study of human adipogenesis.


Subject(s)
Adipocytes/cytology , Mesoderm/cytology , Stem Cells/cytology , 1-Methyl-3-isobutylxanthine/pharmacology , Animals , Blood , Blotting, Western , Cell Differentiation/drug effects , Cells, Cultured , Clone Cells/cytology , Culture Media , Cyclin D1/genetics , Dexamethasone/pharmacology , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Glucocorticoids/pharmacology , Glucose/pharmacology , Humans , Indomethacin/pharmacology , Insulin/pharmacology , Mitogen-Activated Protein Kinase 1/antagonists & inhibitors , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , Proliferating Cell Nuclear Antigen/genetics , RNA, Messenger/analysis , Rabbits , Reverse Transcriptase Polymerase Chain Reaction
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