Roger Unger

..There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents...

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..Graft failure is prevented by blocking lipogenesis. The results suggest that strict antilipogenic intervention might improve outcomes after human islet transplantation...

..To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency...

..This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy...

..The causes of failure of this system and its clinical consequences are discussed...

..Third, I suggest that lipid-induced insulin resistance and the accompanying metabolic syndrome are secondary to leptin resistance, resulting in breakdown in the normal partitioning of surplus lipids in the adipocyte compartment...

..Increased lipid content in the heart and skeletal muscle organs of such patients is now under study...

..Fatty acid derivatives can interfere with the function of the cell and ultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure...

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..We speculate that the metabolic syndrome may be the human equivalent of the lipotoxic syndrome of rodents...

..Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin...

..These results have considerable medical implications, as they suggest new approaches to normalize the extreme volatility of glycemia in diabetic patients...

..We conclude that 11beta-HSD-1 expression and activity are increased in islets of diabetic, but not prediabetic ZDF rats, and that TGZ prevents both the increase in 11beta-HSD-1 and the diabetes...

..In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes...

..Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown...

..These results suggest that the expression level of genes that regulate the adipogenic response to overnutrition profoundly influences the age of onset and severity of diet-induced type 2 diabetes and co-morbidities...

..The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes...

..The only one of these thus far characterized functionally was found to promote lipogenesis...

..2006[this issue of Cell Metabolism]) unexpectedly induce leptin sensitivity with hypophagia and improvement in abnormal glucose and lipid abnormalities...

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..Our findings highlight a role of PP2C and AMPK in the derangements of cardiac lipid metabolism in obesity and provide new insights as to the mechanisms of the liporegulatory disorder leading to lipotoxic cardiomyopathy...

..The findings suggest that leptin controls SCD-1 expression and that troglitazone's antilipotoxic action may involve SCD-2 upregulation...

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..Perfusion with insulin increased FA release by 32%. In vitro and ex vivo findings suggest that nonadipose tissues such as myocardium can export FA when the unoxidized lipid content is excessive...

..We conclude that obesity-level hyperleptinemia protects the heart from lipotoxicity...

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..However, the increase in endogenous insig-1 expression associated with augmented lipogenesis may limit it, but is insufficient to prevent it...

..We conclude that the fat-wasting effect of sustained hyperleptinemia does not involve "local hyperthyroidism" in white adipose tissue and does not require thyroid hormone...

..Increased myocardial triglyceride content was accompanied by elevated LV mass and suppressed septal wall thickening as measured by cardiac imaging...

..Since food restriction did not prevent lipotoxicity, we conclude that alpha-LA treatment, like hyperleptinemia, protects the heart of ACS-transgenic mice from lipotoxicity...

..This preview examines AMP biology and its role in malonyl-CoA generation and attempts to integrate its central actions with its peripheral antilipotoxic actions within the context of leptin physiology in obesity...

..The results suggest that insig-1 expression restricts lipogenesis in mature adipocytes and blocks differentiation in preadipocytes...

..Here, we focus on how both of these processes affect metabolically significant cell-types and highlight how lipotoxicity and sequential lipoapoptosis are as major mediators of insulin resistance, diabetes and cardiovascular disease...

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..These studies parallel the observations in obese animals and provide evidence that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in obese patients...

..We conclude that chronic exposure of islet beta-cells to fatty acids grossly alters a mitochondrial pathway of pyruvate metabolism that is important for normal GSIS...

..Ad.LacZ did not influence the angiogenic effects of leptin. The impaired endothelial function with the leptin resistance may be one of causes of the atherosclerosis in the metabolic syndrome...

..The ability to transform adipocytes into unique fat-burning cells may suggest novel therapeutic strategies for obesity...

..FA-depletion of pancreatic islet transplants makes them resistant to rejection. Using FA-depleted islets we have been able to "cure" insulin-deficient diabetes in rats for ~1 year without immunosuppression. ..

..The result is a massive expansion of adipocytes, which is required for severe obesity to develop. Understanding this pathway is the first step in attempting to block the development of this common American health problem. ..

..The studies should indicate the mechanisms by which FFA cause compensatory changes in beta-cells in the early years of obesity but cause dysfunction apoptosis of beta-cells, and diabetes, in the late years. ..