摘要:

Energy homeostasis is achieved by integration of acute and chronic regulatory mechanisms that control uptake and utilization of substrates and their exchange between tissues. The existence of a number of differentially regulated pathways capable of regulating cellular fatty acid utilization has been documented recently. As in the case of glucose, these pathways provide an adaptive mechanism either at the level of the cell or between tissues to regulate nutrient distribution to match changing cellular needs. Since fatty acid and glucose homeostasis are inextricably linked, these new pathways contribute to overall metabolic regulation and are integral to peripheral glucose utilization and insulin responsiveness.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewCellular lipid metabolism plays an important role in modulating glucose metabolism. Recent models of mice with disruptions in genes involved in cellular fatty acid and triglyceride metabolism have provided insight into the long recognized but incompletely understood relationship between fatty acid metabolism and glucose metabolism.Recent findingsHere we review findings from mice with deficiency in selected genes involved in the cellular uptake, storage, and hydrolysis of fatty acids. Our review is organized from the perspective of a fatty acid, as it makes its way from the circulation into the anabolic and then catabolic pathways in the cell. Although we focus primarily on the phenotypes of knockout mice, we also point out several transgenic models in which the overexpression phenotype provides complementary information.SummaryThe inactivation of enzymes in the anabolic process of fatty acid uptake and storage is more likely to enhance tissue glucose disposal or insulin secretion, whereas disruptions in the catabolic process tend to impair insulin action or secretion. These findings suggest that pharmacological inhibition of fatty acid uptake or storage may be an effective strategy for treating insulin resistance and diabetes.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewSkeletal muscle metabolic energy, needed to maintain contractile activity, is mainly obtained from glucose and long-chain fatty acids. Recent studies have revealed a remarkable parallel between the regulation of uptake of glucose and fatty acids by muscle, in that each is mediated by sarcolemmal transporters that are recruited from an intracellular storage site. The focus of this review is to describe newly obtained insights on the recruitment of fatty acid transporters and their malfunctioning in diabetes.Recent findingsThe major fatty acid transporter involved is fatty acid translocase (CD36). Translocation of this protein to the membrane is triggered by muscle contraction and by insulin, and presumably occurs from distinct intracellular pools. This resembles the well documented exercise and insulin-induced recruitment of glucose transporter-4. Whether another transporter, plasma membrane fatty acid-binding protein, is also subject to such recycling is not yet clear. In a rodent model of insulin-dependent (type 1) diabetes, the increased rate of muscle fatty acid uptake could be associated with an increased total amount of fatty acid translocase (CD36). In a model of non-insulin dependent (type 2) diabetes, this increased rate could be associated with a permanent relocalization of fatty acid translocase to the sarcolemma.SummaryThese findings indicate a pivotal role for the membrane transporter fatty acid translocase in the exercise and insulin-induced increases of muscle fatty acid uptake and utilization, and suggest that malfunctioning of the cellular recycling of fatty acid translocase is involved in the etiology of insulin resistance and type 2 diabetes.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewThis review will outline the recent advances in the area of insulin-stimulated skeletal muscle glucose uptake and its effect on whole body glucose homeostasis, using gene-deletion and transgenic mouse models.Recent findingsInsulin resistance is often the first abnormality detected in cases of type 2 diabetes, and is seen at the level of the peripheral tissues especially muscle. Both the insulin receptor and the insulin-like growth factor I receptor are capable of stimulating glucose uptake into skeletal muscle. One model involves the gene deletion of muscle glucose transport protein 4, which leads to severe insulin resistance and hyperglycemia, and a second model using a transgenic approach abrogates the function of the insulin-like growth factor I receptor and the insulin receptor resulting in severe insulin resistance and progression to diabetes. Both models demonstrate that abrogation of the insulin-like growth factor I receptor and the insulin receptor or a common signalling pathway must be inhibited to cause sufficient insulin resistance to lead to type 2 diabetes; with either glucotoxicity or lipotoxicity being involved in the progression from severe to resistance to full-blown type 2 diabetes.SummaryThus, abrogation of insulin-stimulated glucose uptake in skeletal muscle, at least in mice, may lead to severe insulin resistance and diabetes.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Increased release and action of proinflammatory cytokines are thought to be responsible for the occurrence of insulin resistance in inflammatory and metabolic diseases including obesity-linked diabetes. Recent work has identified several signal transduction pathways activated by cytokines which can impede on insulin receptor signaling in skeletal muscle, liver, and adipose cells. A majority of these complex and interrelated pathways appear to converge at the level of insulin receptor substrate-1 by promoting its serine phosphorylation in order to mediate heterologous inhibition of insulin receptor substrate-1 signaling which, in turn, counterregulates the insulin response. Other possible mechanisms of insulin resistance in cytokine-treated cells include nitration of insulin receptor substrate-1 tyrosine residues by nitric oxide-derived reactive nitrogen species as well as direct interference with insulin signaling molecules further downstream such as protein kinase B/Akt. A detailed knowledge of the complex network of intracellular signaling pathways triggered by cytokines may be instrumental in the development of new approaches to prevent insulin resistance in acute and chronic inflammatory settings.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewAngiotensinogen and components of the renin-angiotensin system are expressed in adipose tissue of rodents and humans, but the role of generated angiotensin II has remained intriguing. Moreover, the functional importance of angiotensin II receptor subtypes in preadipocytes and adipocytes still remains a controversial subject.Recent findingsRecent findings in transgenic mice have emphasized the upregulation of angiotensinogen expression by glucocorticoids. Furthermore, angiotensinogen products, that is angiotensin II and possibly angiotensin II-related products, have been found to act locally in modulating adipose tissue growth in an autocrine/paracrine manner. Cellularity measurements show that fat mass enlargement is associated with adipocyte hypertrophy, consistent with the upregulation of the fatty acid synthetase gene by angiotensin II depicted at the molecular level. Together, these findings suggest a mechanism by which transient or chronic overexpression of angiotensinogen in adipose tissue favors lipogenesis in adipocytes and leads to a ‘vicious’ circle whereby adipose tissue development is further increased.SummaryAdditional studies are warranted to characterize angiotensin II-related receptors, if any, and to clarify the role played by angiotensin II receptor subtypes and metabolites in various metabolic aspects of white adipose tissue.Purpose of reviewAngiotensinogen and components of the renin-angiotensin system are expressed in adipose tissue of rodents and humans, but the role of generated angiotensin II has remained intriguing. Moreover, the functional importance of angiotensin II receptor subtypes in preadipocytes and adipocytes still remains a controversial subject.Recent findingsRecent findings in transgenic mice have emphasized the upregulation of angiotensinogen expression by glucocorticoids. Furthermore, angiotensinogen products, that is angiotensin II and possibly angiotensin II-related products, have been found to act locally in modulating adipose tissue growth in an autocrine/paracrine manner. Cellularity measurements show that fat mass enlargement is associated with adipocyte hypertrophy, consistent with the upregulation of the fatty acid synthetase gene by angiotensin II depicted at the molecular level. Together, these findings suggest a mechanism by which transient or chronic overexpression of angiotensinogen in adipose tissue favors lipogenesis in adipocytes and leads to a ‘vicious’ circle whereby adipose tissue development is further increased.SummaryAdditional studies are warranted to characterize angiotensin II-related receptors, if any, and to clarify the role played by angiotensin II receptor subtypes and metabolites in various metabolic aspects of white adipose tissue.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewA novel peptide hormone, ghrelin, has been identified from the stomach and recognized as an important regulator of growth hormone release and energy homeostasis. It is interesting to note that the stomach may play an important role in not only digestion but also pituitary growth hormone release and central feeding regulation. Thus, we summarize the recent findings on the mechanism of these effects induced by ghrelin.Recent findingsThe coadministration of ghrelin and growth hormone releasing hormone was found to have a synergistical effect on pituitary growth hormone secretion. The infusion of growth hormone releasing hormone in rats resulted in a significant increase in pituitary gene expression of ghrelin and its receptor system, suggesting that this system in the pituitary gland could modulate the regulation of growth hormone secretion by growth hormone releasing hormone. Ghrelin promoted the production of orexigenic neuropeptides (neuropeptide Y and agouti-related protein) in the hypothalamic arcuate nuclei and activated the neurons which produce these orexigenic neuropeptides, resulting in an increase in feeding and body weight. Gastric acid release and pancreatic protein secretions were also regulated by ghrelin through vagal and intrapancreatic neuronal activation, respectively. It is possible that ghrelin may participate in the regulation of cell proliferation, glucose homeostasis, and the immune system.SummaryGhrelin, secreted from the stomach, modulates growth hormone release and feeding promotion. Further elucidation of the mechanisms of ghrelin effects will help to improve the diagnosis and treatment of eating disorders and disturbed conditions of nutritional homeostasis.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewTo provide an in-depth analysis of current developments concerning biochemical mechanisms of cellular catabolism. There have been a number of important developments in this area over the past 12 months, particularly with respect to protein catabolism.Recent findingsProtein degradation in a range of catabolic conditions is mediated primarily through the ubiquitin-proteasome proteolytic pathway. Glucocorticoids have been suggested to activate this system in sepsis, while in cancer cachexia a tumour-produced sulphated glycoprotein, proteolysis-inducing factor, induces protein catabolism in skeletal muscle by increasing expression of proteasome subunits and the ubiquitin carrier protein, E214k. Apoptosis may also be important in the loss of muscle protein during the early stage of cachexia. Induction of proteasome expression by glucocorticoids appears to be a direct result of the downregulation of the activity of nuclear factor κB, while proteolysis-inducing factor acts through 15-hydroxyeicosatetraenoic acid as an intracellular transducer.SummaryFormation of 15-hydroxyeicosatetraenoic acid is inhibited by eicosapentaenoic acid, which has been shown to attenuate the development of weight loss in patients with pancreatic cancer. When eicosapentaenoic acid is combined with an energy dense nutritional supplement, there is an increase in body weight of cachectic cancer patients through an increase in lean body mass. Eicosapentaenoic acid also prevents protein catabolism and activation of the ubiquitin-proteasome proteolytic pathway during acute starvation in mice, suggesting a similar pathway is involved. Thus eicosapentaenoic acid may be effective in the treatment of protein catabolism in conditions other than cancer.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Purpose of reviewCatabolism conjures up an end-metabolic process in which muscle and fat tissue are broken down into their constituent parts to provide nutrients for the body, secondary to a noxious stimulus that prevents the organism from adequately nourishing itself. However, catabolism is a primary event, initiated in the brain in response to perceived or real stresses or noxious stimuli, which has a secondary effect of inhibiting food intake and consequently the break down of skeletal muscle and adipose tissues to provide nutrients for the body to survive.Recent findingsThis is achieved via a cascade of neurohormonal monoaminergic and peptidergic mediators in the central nervous system, invoking the cortex, the limbic system and the hypothalamus. Among the most detailed mediators studied are corticotropin-releasing factor and serotonin which, via the hypothalamic-pituitary-adrenal axis and the sympathetic and parasympathetic nervous system, stimulate catecholamines and cortisol and inhibit anabolic hormones, insulin, leptin, ghrelin, including neuropeptide Y and other neuropeptides, among them the paracrine-acting cytokines. Simultaneously, there occurs stimulation of the counter-regulatory hormones cortisol, glucagon and the melanocortin family of neuropeptides.SummaryThe net effect is anorexia, with the inhibition of food intake, body weight loss, delayed gastric emptying and functions, the stimulation of gluconeogenesis, glycogenolysis and ketogenesis as sources of metabolic fuel, which if unabated leads ultimately to cachexia. The use of antagonists and the removal of stress or noxious stimuli experimentally test different pathways of this dynamic metabolic picture. Several studies have demonstrated important progress towards our understanding of the central mechanisms involved in anorexia and weight loss, which we summarize in this review.

ISSN:1363-1950    

出版商:OVID    

年代:2002

数据来源: OVID