Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adipsin is a serine protease that is secreted by adipocytes into the bloodstream; it is deficient in several animal models of obesity, representing a striking example of defective gene expression in this disorder. Recombinant mouse adipsin was purified and its biochemical and enzymatic properties were studied in order to elucidate the function of this protein. Activated adipsin has little or no proteolytic activity toward most substrates but has the same activity as human complement factor D, cleaving complement factor B when it is complexed with activated complement component C3. Like authentic factor D, adipsin can activate the alternative pathway of complement, resulting in red blood cell lysis. Decreased (58 to 80 percent) complement factor D activity, relative to lean controls, was observed as a common feature of several experimental models of obesity, including the ob/ob, db/db, and monosodium glutamate (MSG)-injected mouse and the fa/fa rat. These results suggest that adipsin and the alternative pathway of complement may play an unexpected but important role in the regulation of systemic energy balance in vivo.
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PMID:Adipsin and complement factor D activity: an immune-related defect in obesity. 273 15

The mouse adipsin gene encodes a member of the serine protease family that is expressed predominantly in adipose tissue and is secreted into the bloodstream. Adipsin expression is sharply down-regulated in several models of genetic and acquired obesity, representing the first example of an adipocyte gene whose expression is greatly altered in this disorder. In this study, we have asked whether a DNA fragment from the adipsin gene can direct tissue-specific expression of a heterologous gene and mediate the suppression of this expression in genetic and chemically induced obesity. Transgenic mice have been constructed with 950 bases of DNA from the 5' flanking region of the adipsin gene linked to the bacterial chloramphenicol acetyltransferase (CAT) gene in a mouse strain bearing a recessive obesity gene (diabetes, db). By crossing db/+ transgenic mice with nontransgenic db/+ mice, we obtained progeny that allowed a direct comparison of CAT expression in the tissues of lean and obese littermates. The lean mice express CAT activity predominantly in adipose tissue, while the obese mice show a marked reduction in CAT expression relative to the lean controls. When similar experiments are performed with an adipsin-CAT fusion gene containing a heterologous AKV (AKR mouse leukemia virus) enhancer, the tissue specificity of CAT expression in lean mice is broadened to include the thymus, spleen, brain, and other tissues; down-regulation occurs in all of these tissues in mice homozygous for the obesity gene or in mice that have been injected with monosodium glutamate (MSG), which induces obesity. These results indicate that 950 bases of the 5' flanking region of the adipsin gene carry information that specifies both expression in adipose tissue and a response to a gene or chemical that induces obesity. These results also suggest that the trans-acting factors that are regulated aberrantly in these forms of obesity are not restricted to adipose tissue and could play a role in obesity-linked dysfunctions observed in other tissues as well.
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PMID:Obesity-linked regulation of the adipsin gene promoter in transgenic mice. 279 20

Adipsin expression at the protein and mRNA levels is greatly reduced in several distinct syndromes of obesity in the mouse: genetic obesity due to the db/db and ob/ob genes, and a chemically induced model secondary to neonatal exposure to monosodium glutamate. We considered first the possibility that the adipsin gene might be identical to the db or ob locus and the lowered expression of this protein might result from a mutation in this gene. We show here that the adipsin structural gene is located on chromosome 10 and hence is physically distinct from any obesity genes so far identified in the mouse. A major role for the adrenal gland and adrenal glucocorticoids in the aberrant regulation of adipsin in these models of obesity is indicated by several experiments. Adrenalectomy of the ob/ob mouse raises the circulating levels of adipsin protein and the amount of this mRNA in epididymal fat pads (5-fold), although neither is increased to the levels seen in lean controls. Exogenous administration of corticosterone completely blocks the effects of adrenalectomy on adipsin, suggesting that the effect of this endocrine ablation is through reduction of adrenal glucocorticoids. Corticosterone administration also causes suppression in the levels of adipsin mRNA and protein in lean mice, although this decrease is never as severe as that seen in obese mice. The effect of exogenous corticosterone in lean mice occurs within 2 days and hence is not secondary to the obesity which these hormones eventually elicit. These results indicate that glucocorticoids can regulate adipsin expression in vivo and strongly suggest that the hyperglucocorticoid state seen in certain obese models plays a significant role in lowering adipsin mRNA and protein levels. Quantitative analysis of these experiments suggests that other as yet unknown neuroendocrine factors also function to suppress adipsin in obesity.
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PMID:Adrenal glucocorticoids regulate adipsin gene expression in genetically obese mice. 291 85

Adipsin gene expression as assessed by mRNA amounts was examined in adipose tissue of genetically obese rats at the onset (16 days of age) or at later stages (30 and 60 days of age) of obesity. Amounts of mRNA were equivalent in obese and lean rats at 16 days of age. In adult rats, we observed a 2-fold decrease in adipsin mRNA in the obese rats compared with control lean rats, which was abolished by weaning the animals on a high-fat diet. Our data show that, in sharp contrast with genetically obese mice, adipsin mRNA is not suppressed in genetically obese Zucker rats.
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PMID:Adipsin mRNA amounts are not decreased in the genetically obese Zucker rat. 293 Apr 96

Adipsin, a serine protease homolog, is synthesized and secreted by adipose cells and is found in the bloodstream. The expression of adipsin messenger RNA (mRNA) and protein was analyzed in rodents during metabolic perturbations and in several experimental models of obesity. Adipsin mRNA abundance is increased in adipose tissue during fasting in normal rats and in diabetes due to streptozotocin-induced insulin deficiency. Adipsin mRNA abundance decreased during the continuous infusion of glucose, which induces a hyperglycemic, hyperinsulinemic state that is accompanied by an increased adipose mass; it is suppressed (greater than 100-fold) in two strains of genetically obese mice (db/db and ob/ob), compared to their congenic counterparts, and is also reduced when obesity is induced chemically by injection of monosodium glutamate into newborn mice. Circulating adipsin protein is decreased in these animal models of obesity, as determined by immunoblotting with antisera to adipsin. Little change in adipsin expression is observed in a model of obesity obtained by pure overfeeding of normal rats (cafeteria model). These data suggest a possible role for adipsin in the above-mentioned disordered metabolic states, and raise the possibility that adipsin expression may be used to distinguish obesities that arise from certain genetic or metabolic defects from those that result from pure overfeeding.
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PMID:Severely impaired adipsin expression in genetic and acquired obesity. 329 6

The adipsin-ASP pathway provides a mechanism by which the adipocyte is able to regulate its rate of de novo triglyceride synthesis and reesterification. The adipocyte can synthesize and secrete the three proteins necessary for the formation of the effector molecule, acylation stimulating protein (ASP). ASP increases membrane transport of glucose and the activity of diacylglycerol acyltransferase and by virtue of both of these effects markedly increases the rate of triglyceride synthesis. Awareness of the pathway will allow, we believe, a new understanding of the regulation of triglyceride removal from plasma. Accordingly, the concept of microenvironmental metabolic regulation of triglyceride hydrolysis at the endothelial surface and triglyceride synthesis within the adipocyte will be presented. In addition, the pathogenetic sequence by which dysfunction of this pathway can lead to dyslipoproteinaemia will be reviewed. Emphasis, however, will be placed on the role this pathway may play in the pathogenesis of obesity and the adaptation to negative caloric balance in the obese.
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PMID:The adipsin-ASP pathway and regulation of adipocyte function. 769 62

Transcription of the adipocyte-specific adipsin gene is dramatically reduced in the adipose tissue of a number of genetically and chemically-induced obese rodents. To map the region of the adipsin gene that confers this response to obesity, transgenic mice were made containing -114, -250, -400, -700, and -938 base pairs (bp) to +35 bp of the promoter linked to the bacterial chloramphenicol acetyltransferase gene. Transgenic mice containing as few as 114 bp of the adipsin promoter had high levels of chloramphenicol acetyltransferase activity in adipose tissue. However, only those mice with 938 bp of the adipsin upstream regulatory region showed suppression of expression in adipose tissue in mice that were induced to become obese with monosodium glutamate. Using gel retardation assays, we showed that a 56-bp fragment of DNA mapping between -687 and -743 bp upstream from the start of adipsin expression was bound by protein factors in nuclear extracts prepared from adipose tissue. There was much greater retardation of this fragment with nuclear extracts prepared from adipose tissue of lean versus obese mice. These results indicate that a tissue-specific transcription factor(s) that regulates adipsin expression is less active in the adipose tissue of obese animals.
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PMID:Independent regulation of adipose tissue-specificity and obesity response of the adipsin promoter in transgenic mice. 796 1

Adipsin, which is identical to complement factor D, is synthesized by fat cells, circulates in the bloodstream and is profoundly deficient in mice with genetic and hypothalamic obesity. With the recent cloning of human adipsin, a quantitative human immunoassay has been developed. In the present study, we measured adipsin blood concentrations in humans with increased and decreased adipose stores as well as adipsin secretion by adipose tissue obtained from lean and obese individuals. The results demonstrate that adipsin is released by human adipose tissue fragments as has previously been shown in mice, and that, in contrast to obese mice, blood adipsin concentrations were not reduced in the obese humans tested in this study. We also observed that blood adipsin concentrations can vary as a function of feeding or adiposity, in that they tend to be mildly elevated in obese individuals or mildly reduced in individuals with total lipo-atrophy, cachexia related to AIDS and anorexia nervosa. Thus, the circulating concentration of adipsin tends to correlate positively with degree of adiposity. Clearly, no deficiency in blood adipsin concentrations or adipsin secretion by adipose tissue was observed in the obese individuals studied.
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PMID:Concentrations of adipsin in blood and rates of adipsin secretion by adipose tissue in humans with normal, elevated and diminished adipose tissue mass. 804 95

Adipsin is a molecular marker of obesity in rodents. Content of adipsin protein in blood and mRNA in adipocytes is significantly reduced in several genetic and experimentally induced obese models. It has been suggested that this reduction in adipsin is causative to obesity development. Insulin reduces adipsin expression in vitro and is negatively correlated with adipsin expression in vivo. Because bovine somatotropin (bST) opposes many actions of insulin and can reduce body fat content, we tested the hypothesis that bST enhances adipsin expression. In two experiments using 210 rats, bST and a similar hormone, bovine placental lactogen (bPL), both caused a small (14 to 27%) but statistically significant reduction in circulating adipsin protein. Because exogenous bST can increase circulating insulin we next used a diabetic model to test the bST effect on adipsin. In rats treated with streptozotocin and injected daily with insulin (STZ+I), bST had no effect on circulating adipsin. Additional variables related to growth were influenced differently by bST in normal vs. STZ+I animals. In conclusion, the drop in circulating adipsin following bST administration in normal rats is dependent upon the animals' ability to secrete insulin.
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PMID:Adipsin expression and growth in rats as influenced by insulin and somatotropin. 837 11

Transgenic mice overexpressing transforming growth factor alpha (TGF-alpha) under control of the metallothionein promoter had, on average, 20% reductions in body and carcass weights compared to nontransgenic littermates. This loss resulted from significant decreases in the comparative weights of bone, muscle, and especially fat. Transgenic epididymal fat pads were reduced by 40-80%, and total body fat content by 50%, relative to control animals. Distal hindlimb muscle weights were 20% below normal, and other skeletal muscles were visibly smaller in size. Weight reductions were accompanied by decreases in the cellularity of transgenic fat pads and muscles and by decreases in the number and area of striated muscle fibers. These findings were not obviously attributable to differences in metabolic rates since transgenic and control mice displayed similar levels of energy expenditure per unit lean body mass. The effects of TGF-alpha on the development of these tissues could be mimicked in culture for fat but not muscle. Thus, TGF-alpha did not inhibit the differentiation of the mouse skeletal myoblast cell line C2C12 as evidenced by the expression of muscle-specific actin and fusion to form multinucleated myotubes. However, TGF-alpha repressed the differentiation of the preadipocyte cell line 3T3-F442A in a dose-dependent and reversible manner as judged by morphological conversion and diminished expression of mRNAs encoding the adipocyte-specific markers adipsin and glycerophosphate dehydrogenase. This repression, which occurred without marked stimulation of proliferation, was incomplete even in the presence of high concentrations of growth factor. Despite its effects on adipose development, introduction of the metallothionein-TGF-alpha transgene into the ob/ob genetic background did not suppress the marked obesity characteristic of this mutation. Finally, endogenous TGF-alpha epidermal growth factor receptor mRNAs were detected in normal adipose tissue, suggesting that regulation of adipogenesis by this growth factor may be physiological.
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PMID:Regulation of fat and muscle development by transforming growth factor alpha in transgenic mice and in cultured cells. 846 58


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