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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hypothesis that the stimulatory action of free fatty acids (FFA) in the hypothalamic-pituitary-adrenocortical (HPA) axis occurs in part at the adrenal cortex was evaluated. Pathophysiological concentrations of oleic and linoleic acids, but not stearic or caprylic acid, stimulated steroidogenesis from cultured rat adrenocortical cells (concentrations eliciting 50% of maximal responses, approximately 60 and 120 microM, respectively), with a latency of 90 min. Maximal stimulation of steroidogenesis by both acids was < 50% of that produced by adrenocorticotropic hormone (ACTH) and was blocked by cycloheximide. The maximal steroidogenic response to ACTH was inhibited approximately 50% by oleic acid. The actions of oleic and linoleic acids were not associated with an increase in adenosine 3',5'-cyclic monophosphate (cAMP) secretion but appeared to require intracellular oxidation. None of the lipids influenced cell viability or corticosterone radioimmunoassay. The latency of the steroidogenic response, the putative requirement for intracellular oxidation, and the apparent lack of involvement of cAMP suggest a mechanism of action of FFA distinct from that of ACTH, yet still requiring protein synthesis. It is concluded that the modulation of steroidogenesis by these abundant naturally occurring lipids may be an important component of the control mechanisms within the HPA pathway in disorders of lipid homeostasis (e.g., obesity, starvation, or diabetes).
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PMID:Stimulation of steroidogenesis in cultured rat adrenocortical cells by unsaturated fatty acids. 761 25

The lipolysis in adipose tissue is controlled by the hormone-sensitive lipase activity which is dependent on the intracellular cAMP level. In human adipose tissue, cAMP level is increased by catecholamines (through beta-adrenoceptor stimulation) or decreased by insulin, catecholamine (through alpha 2-adrenoceptor stimulation), neuropeptide Y, prostaglandins and adenosine. The mobilization of lipids from adipose tissue is an adaptative mechanism in response to starvation or hypocaloric diet, which involves reduction of the antilipolytic effect of insulin and the increase of catecholamine sensitivity. The regulatory pathways of lipolysis and their adaptation to caloric reduction are not defective in obesity state. Pharmacological approaches proposed for the activation of lipolysis are limited; they mainly consist either to stimulate the fat cell beta-adrenoceptors (beta-sympathomimetic drugs) or to indirectly activate the sympathetic nervous system (ephedrine and its derivatives, methylxanthines, alpha 2-antagonists). However, the side effects elicited by these drugs frequently limit their clinical use.
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PMID:[Lipid mobilization, physiopathological and pharmacological aspects]. 775 46

The mouse agouti coat color gene encodes a novel paracrine signaling molecule whose pulsatile expression produces a characteristic pattern of banded pigment in individual hairs. Several spontaneous agouti alleles produce adult-onset obesity and diabetes, and have provided important single-gene animal models for alterations in energy metabolism. Utilizing linkage groups conserved between mice and humans, we have cloned the human homolog of the mouse agouti gene from a human chromosome 20 yeast artificial chromosome known to contain S-adenosyl homocysteine hydrolase (AHCY). The human agouti gene, named Agouti Signaling Protein (ASP), encodes a 132 amino acid protein, the mRNA for which is expressed in testis, ovary, and heart, and at lower levels in liver, kidney, and foreskin. As predicted by the interactions of mouse agouti with the extension gene (which encodes the melanocyte receptor for alpha-melanocyte stimulating hormone [alpha-MSH]), expression of ASP in transgenic mice produces a yellow coat, and expression of ASP in cell culture blocks the alpha-MSH-stimulated accumulation of cAMP in mouse melanoma cells. The localization of ASP relative to other loci on chromosome 20 excludes it as a candidate for the MODY1 locus, a gene responsible for one form of early-onset non-insulin-dependent diabetes mellitus or maturity-onset diabetes of the young. The expression of ASP in human tissues suggests a function for agouti homologs in species that do not exhibit the characteristic phenotype of banded hairs.
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PMID:Structure and function of ASP, the human homolog of the mouse agouti gene. 775 71

A primary culture of undigested fat tissue fragments was used to obtain fat cells in vitro. On day 2 of culture, immature fat cells, which are fibroblast-like fat cells containing fine lipid droplets, appeared, surrounding the fat tissue fragments, and began to proliferate extensively. Afterwards, these fibroblast-like fat cells grew to become multilocular fat cells containing larger intracytoplasmic lipid droplets, and differentiated further into unilocular fat cells containing a single large intracytoplasmic lipid droplet. Treatment with dibutyryl-cAMP, which is a second messenger of the lipolytic factor, caused the cultured fat cells to retract, and the intracytoplasmic lipid droplets of those fat cells became finely granulated and decreased along with an increase of hormone-sensitive lipase activities. Conversely, administration of insulin caused the lipid droplets in the fat cells to increase and become larger along with an increase of alpha-glycerophosphate dehydrogenase activities. These findings indicate the occurrence of lipolysis and lipogenesis of fat cells in vitro. Immuno-cytochemistry revealed that vimentin surrounded intracytoplasmic lipid droplets, and became distinct with an increase of lipid droplets through lipogenesis in the fat cells. Vimentin seems to be correlated to the behavior of lipid droplets in the fat cells. Fat cells in this study showed the appropriate cellular structures and functions in response to stimulation of lipolysis and lipogenesis under culture conditions. It is expected that in vitro culture of fat cells will facilitate cell biological elucidation of obesity in the future.
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PMID:Cellular structure and function of rat fat cells in the primary culture. 779 65

Bearing in mind the importance of upper-body obesity for the insulin resistance (or metabolic) syndrome and the abnormalities in free fatty acid metabolism associated with this disorder, the regulation of lipolysis in isolated subcutaneous adipocytes was investigated in 13 72-yr old upper-body obese men with insulin resistance and glucose intolerance and in 10 healthy 72-yr-old men. There was a marked resistance to the lipolytic effect of noradrenaline in the metabolic syndrome due to defects at two different levels in the lipolytic cascade. First, an 80-fold decrease in sensitivity to the beta 2-selective agonist terbutaline (P < 0.001) which could be ascribed to a 50% reduced number of beta 2-receptors (P < 0.005) as determined with radioligand binding. The groups did not differ as regards dobutamine (beta 1) or clonidine (alpha-2) sensitivity, nor beta 1-receptor number. The mRNA levels for beta 1- and beta 2-receptors were similar in the two groups. Second, the maximum stimulated lipolytic rate was markedly reduced in the metabolic syndrome. This was true for isoprenaline (nonselective beta-agonist), forskolin (activating adenylyl cyclase), and dibutyryl cAMP (activating protein kinase). In regression analysis, the observed abnormalities in lipolysis regulation correlated in an independent way with the degree of glucose intolerance (r = -0.67) and beta 2-receptor number with insulin resistance (r = 0.67). In conclusion, the results of this study indicate the existence of lipolytic resistance to catecholamines in the adipose tissue of elderly men with the metabolic syndrome, which may be of importance for impaired insulin action and glucose intolerance. The resistance is located at a posttranscriptional level of beta 2-receptor expression and at the protein kinase-hormone sensitive lipase level.
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PMID:Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. 820 Sep 97

The pivotal role of the sympathoadrenal system in the defense of le milieu interieur has, in the last 15 years, been extended to include the fat stores-a notion that forms the basis of current strategies for thermogenic stimulation in obesity therapy. The search for effective and safe sympathetic stimulants has been directed at two main levels: (i) the development of novel beta-agonists selective for thermogenesis, and (ii) the evaluation of drugs already in clinical use for other purposes (e.g. ephedrine) which could conceivably increase the release of catecholamines to levels that enhance thermogenesis without significant cardiovascular effects. A re-direction of these strategies seem inevitable because at therapeutic doses, the thermogenic effects of these sympathomimetics seem to be considerably dampened by negative feedback mechanisms that operate both extracellularly (e.g. via adenosine & prostaglandins) as well as inside the cells (via cAMP phosphodiesterases). Such a contention is supported by studies both in man and in animals showing that methylxanthines and aspirin, drugs known to be capable of interfering with these modulators, potentiate the thermogenic effects of ephedrine. Future research aimed at clarifying the types and subtypes of these negative modulators of sympathomimetic-induced thermogenesis and their targeting by more selective antagonists would no doubt be pivotal in providing the safe drug combination with the necessary thermogenic properties to assist the management of obesity.
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PMID:Ephedrine, xanthines and prostaglandin-inhibitors: actions and interactions in the stimulation of thermogenesis. 838 78

Cyclic AMP is an important second messenger in the coordinated regulation of cellular metabolism. Its effects are mediated by cAMP-dependent protein kinase (PKA), which is assembled from two regulatory (R) and two catalytic (C) subunits. In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C gene (encoding C alpha and C beta), expressed in tissue-specific patterns. The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we generated RII beta knockout mice. Here we report that mutants appear healthy but have markedly diminished white adipose tissue despite normal food intake. They are protected against developing diet-induced obesity and fatty livers. Mutant brown adipose tissue exhibits a compensatory increase in RI alpha, which almost entirely replaces lost RII beta, generating an isoform switch. The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enzyme. This causes induction of uncoupling protein and elevations of metabolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulating energy balance and adiposity.
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PMID:Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. 875 24

The syndrome of insulin resistance comprises the following H-phenomena: 1. Hyperinsulinism compensating the inborn postreceptor insulin resistance, 2. Hyperglycaemia-non-insulin-dependent diabetes mellitus, 3. Hyperlipoproteinaemia with android obesity, 4. Hypertension, 5. Hirsutism with the syndrome of polycystic ovaries as a manifestation of a hyperandrogenic situation in the female organism. Molecular syndromes of this syndrome of insulin resistance are obscure. They are the subject of intensive studies because H-phenomena are an aggregation of the main risk factors of atherogenesis. Recently attention is focused also on amylin--a 37 amino acid peptide with a 50% homologous amino acid sequence with a calcitonin-gene--related peptide (CGRP), which is the product of a gene made up of three introns on the 12th chromosome. Amylin acts in the beta-cells of the pancreas as a co-secretion of insulin. If in excess, it is deposited in the form of an amyloid in the beta-cells. In the early stage of NIDDM it alters the physiological response of the beta-cell to glycaemic stimuli and food, in later stages of the disease, after accumulation, it causes apoptosis of the beta-cell and reduces thus the secretory capacity of the Langerhans islets. It is excreted in the urine and thus, if the glomerular filtration is reduced, it cumulates in the blood stream and thus enhances insulin resistance already in the early stages of chronic renal insufficiency, or in diabetic nephropathy. In type II diabetes similarly as insulin levels also amylin levels are elevated, while in type I diabetes with early autoimmune destruction of the beta-cells the insulin and amylin levels are reduced or even zero. Amylin reduces in the muscle, probably by inhibition of glycogen synthase, the insulin stimulated non-oxidative utilization of glucose into muscle glycogen and conversely by stimulation of phosphorylase it stimulates glycogenolysis and thus also lactate production and gluconeogenesis in the liver which all are anti-insulin effects which intensify the insulin resistance of the main target tissues. Amylin, similarly as CGRP or calcitonin, reduces Ca blood levels and has a vasodilatating effect; it reduces the BP but in different minimal and maximal doses and by a different mechanism and via special receptors because the link of amylin to calcitonin receptors is 100 times lower and does not produce a rise of cAMP in the target cell. The effect on the enhancement of insulin resistance in muscle was proved also by direct measurements using an hyperinsulinaemic euglycaemic clamp. After prolongation of the clamp to more than two hours the effect on insulin resistance disappeared, although the hypocalcinaemic effect persisted. Amylin is able by its biological action to modify the secretion as well as the effectiveness of insulin to pathological values. These two characteristics are typical for impaired glucose tolerance in type II diabetes. Studies are under way to find out whether the effect of amylin is involved directly also in the pathogenesis of the other H-phenomena or only via accentuation of hyperinsulinism. In any case amylin is a new link the role of which in the pathogenesis of NIDDM and the syndrome of insulin resistance awaits evaluation. Due to its effect on gastric evacuation it participates also in the postprandial glycaemic control in particular in type I diabetes where it it begins to be used in therapy. Perhaps it will be possible to administer it in these patients along with insulin to improve diabetes compensation.
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PMID:[Amylin as an additional possible pathogenic factor in NIDDM and the insulin resistance syndrome]. 896 27

The ratio of alpha- to beta-receptors is thought to regulate the lipolytic index of adipose depots. To determine whether increasing the activity of the beta 1-adrenergic receptor (AR) in adipose tissue would affect the lipolytic rate or the development of this tissue, we used the enhancer-promoter region of the adipocyte lipid-binding protein (aP2) gene to direct expression of the human beta 1 AR cDNA to adipose tissue. Expression of the transgene was seen only in brown and white adipose tissue. Adipocytes from transgenic mice were more responsive to beta AR agonists than were adipocytes from nontransgenic mice, both in terms of cAMP production and lipolytic rates. Transgenic animals were partially resistant to diet-induced obesity. They had smaller adipose tissue depots than their nontransgenic littermates, reflecting decreased lipid accumulation in their adipocytes. In addition to increasing the lipolytic rate, overexpression of the beta 1 AR induced the abundant appearance of brown fat cells in subcutaneous white adipose tissue. These results demonstrate that the beta 1 AR is involved in both stimulation of lipolysis and the proliferation of brown fat cells in the context of the whole organism. Moreover, it appears that it is the overall beta AR activity, rather than the particular subtype, that controls these phenomena.
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PMID:Transgenic mice overexpressing the beta 1-adrenergic receptor in adipose tissue are resistant to obesity. 899 85

The metabolic response of adipose tissue to stimuli leading to lipid mobilization is important in determining the direction of metabolism and the degree to which adipose tissue can store lipids and release fatty acids in times of need. The lipolytic machinery is controlled by the activity of hormone-sensitive lipase, which in turn is controlled by the cellular levels of cAMP. The production of cAMP is abnormal in the adipose tissue of some animal models of obesity. In the ob/ob mouse, the defective cAMP production has been associated with deficient levels of some of the isoforms of the guanine nucleotide transducing G-proteins and also with the low expression and functionality of the beta 3-adrenergic receptor (beta 3-AR). The recent discovery of the ob gene product leptin calls into question the role of the ob gene in the regulation of the cAMP cascade in adipose tissue. The importance of the beta 3-AR and leptin in regulating human adipose tissue metabolism remains to be clarified.
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PMID:Of mice and women: the beta 3-adrenergic receptor leptin and obesity. 901 68


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