International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity最新文献

Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-alpha) in obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-alpha activity is blocked in obesity, either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and I kappa beta kinase (I kappa K) as critical regulators of insulin action activated by TNF-alpha and other inflammatory and stress signals, and the identification of potential targets. Here, the role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms underlying JNK-induced insulin resistance will be discussed.

Insulin is a key anabolic hormone that plays a crucial role in growth, differentiation and metabolism. Insulin action is initiated by the binding of the hormone to its tyrosine kinase cell surface receptor, leading to the multisite autophosphorylation of the receptor. This results in the activation of the receptor kinase and subsequent tyrosine phosphorylation of insulin receptor substrates, most of which are docking proteins for signaling molecules. For the last several years, our laboratory has been interested in the mechanisms that lead to the modulation of insulin signal transduction, and hence might be involved in insulin resistance found in obesity and type II diabetes. For this review, we have focused on three 'modulators' of insulin action: hyperinsulinemia, suppressor of cytokine signaling proteins and advanced glycation end products.

Insulin resistance is a pivotal feature in the pathogenesis of type 2 diabetes, and it may be detected 10-20 y before the clinical onset of hyperglycemia. Insulin resistance is due to the reduced ability of peripheral target tissues to respond properly to insulin stimulation. In particular, impaired insulin-stimulated muscle glycogen synthesis plays a significant role in insulin resistance. Glucose transport (GLUT4), phosphorylation (hexokinase) and storage (glycogen synthase) are the three potential rate-controlling steps regulating insulin-stimulated muscle glucose metabolism, and all three have been implicated as being the major defects responsible for causing insulin resistance in patients with type 2 diabetes. Using (13)C/(31)P magnetic resonance spectroscopy (MRS), we demonstrate that a defect in insulin-stimulated muscle glucose transport activity is the rate-controlling defect. Using a similar (13)C/(31)P MRS approach, we have also demonstrated that fatty acids cause insulin resistance in humans due to a decrease in insulin-stimulated muscle glucose transport activity, which could be attributed to reduced insulin-stimulated IRS-1-associated phosphatidylinositol 3-kinase activity, a required step in insulin-stimulated glucose transport into muscle. Furthermore, we have recently proposed that this defect in insulin-stimulated muscle glucose transport activity may be due to the activation of a serine kinase cascade involving protein kinase C theta and IKK-beta, which are key downstream mediators of tissue inflammation. Finally, we propose that any perturbation that leads to an increase in intramyocellular lipid (fatty acid metabolites) content such as acquired or inherited defects in mitochondrial fatty acid oxidation, defects in adipocyte fat metabolism or simply increased fat delivery to muscle/liver due to increased energy intake will lead to insulin resistance through this final common pathway. Understanding these key cellular mechanisms of insulin resistance should help elucidate new targets for treating type 2 diabetes.

International Journal of Obesity (2003) 27, S1. doi:10.1038/sj.ijo.0802329

Two key findings regarding the cardiovascular risks associated with obesity have emerged in recent years: one relates to the importance of visceral obesity as a risk factor for cardiovascular disease, and the other to the recognition that adipose tissue can be regarded as a large endocrine organ that directly contributes to cardiovascular risk by secreting a number of molecules known to modulate vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system. Therefore, abdominal fat deposition, which is characterized by increase in waist circumference, should be the target of clinical intervention in obese individuals.

Obesity is a risk marker for progressive renal function loss in patients with known renal disease. There is, however, increasing evidence that obesity may also damage the kidney in otherwise healthy subjects. There appears to be an intriguing parallel between the renal effects of obesity and those of diabetes. First, an increased renal blood flow and glomerular filtration rate has been described in obesity and, second, microalbuminuria is found to be related to obesity. These two events are known to predict future loss of renal function in diabetes. The mechanism responsible for the renal damage in obesity has not been established but there is evidence suggesting that this might be related to both hormonal changes as well as low-grade inflammation.

Sibutramine has a dual mode of action. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. The drug's neurochemical actions can also be distinguished from those of previous centrally acting anti-obesity agents. Clinical trials show that two out of three patients taking sibutramine lose >/= 5% weight and that the drug can enhance the maintenance of weight loss. Early weight loss predicts long-term success and can be used to guide clinical practice. To maximize the benefits of sibutramine, it is important that patients receive adjunctive diet and lifestyle therapy.

In most patients, coronary atherosclerosis or congestive heart failure develop as an integrated response to multiple cardiovascular risk factors. Obesity increases the prevalence of most cardiovascular risk factors and is the predominant cause of diabetes mellitus and arterial hypertension. Moreover, obesity shifts the manifestation of these risk factors to younger age groups, such that subsequent damage results prematurely in clinically overt cardiac diseases. In addition, due to clustering of obesity-related risk factors, obesity may amplify the risk by synergistic mechanisms acting in parallel. Finally, an elevated body mass index (BMI) results in an increase in heart rate and blood volume, as well as increased systolic and diastolic blood pressure. These changes affect cardiac geometry and mass in addition to the alterations of the coronary vasculature. At the population level, the role of obesity in promoting multiple risk factors and, subsequently, the development of heart diseases cannot be underestimated. In individual patients, however, the clinical presentation may be dominated by obesity-related hypertension, diabetes, metabolic and inflammatory derangements or clinical symptoms of heart failure or coronary artery disease. Weight reduction remains a crucial component of the therapeutic strategy to ameliorate insulin resistance, hypertension and left ventricular hypertrophy, among other risk factors, with profound implications for the individual's prognosis.