W I Sivitz

..These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes...

..Lifestyle modifications and certain new pharmacologic agents may be effective in modulating these effects and could prove useful in primary prevention of type 2 diabetes...

....

..Our data suggest that plasma leptin is reduced in untreated type 2 diabetes probably as a consequence of reduced insulin secretion and that circulating leptin concentrations are differentially affected by monodrug therapy...

..However, the in vivo modulation of leptin and UCPs appears complex and, beyond a causal effect of SNA per se, may depend on concurrent changes in plasma insulin, glucose, and circulatory hemodynamics...

..In summary, UCP subtype mRNA and protein are regulated in tissue- and subtype-specific fashion by leptin and food restriction. Under certain conditions, the effects of these perturbations on UCP mRNA and protein are discordant...

..Arterial dysfunction occurs in obesity and diabetes. However, there is uncertainty about the relative contribution of endothelial dysfunction, smooth muscle dysfunction, or adrenergic hyperresponsiveness...

..We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes...

..This is evident on multiple energy substrates and in different respiratory states. CoQ is not reduced in diabetic mitochondria or with weight loss due to food restriction. The implications of these findings are discussed...

..These effects did not appear dependent on altered body weight. Leptin also altered salt and water metabolism under fasting conditions resulting in increased water intake and more dilute urine...

..Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness...

..These data demonstrate that leptin increases thermogenic sympathetic nerve activity and reveal an unexpected stimulatory effect of leptin on overall sympathetic nerve traffic...

..Our data raise the possibility that gender differences in adiponectin may be lost in diabetes. Finally, pharmacologic treatment of diabetes may modulate CRP independent of adiposity...

..Leptin appears to oppose the depressor effect of weight loss...

..These data support the concept that the chronic hemodynamic actions of leptin are likely to be related to sympathetic activation...

..Six days of insulin administration to normal rats under conditions of ad lib. feeding, but without otherwise preventing the blood glucose from decreasing, resulted in no significant change in levels of either ob or GLUT-4 mRNA...

..Our results also suggest an important role for UCP in lipid metabolism and, possibly, insulin secretion...

..Our data also suggest that leptin increases renal SNA through activation of hypothalamic melanocortin receptors. In contrast, sympathoactivation to thermogenic BAT by leptin appears to be independent of the melanocortin system...

..These results suggest that corticotrophin-releasing factor may mediate the sympathoexcitatory effect of leptin on thermogenic tissue without altering its cardiovascular actions...

..Alterations in leptin generation or action may, in part, underlie the sympathetic, endocrine and renal consequences of obesity...

..Thus, we conclude that leptin does not change regional blood flows, and that leptin also does not appear to have vascular or neural actions to cause peripheral functional sympatholysis...

....

..Although we are at an early stage of understanding, we speculate that abnormalities in the actions of leptin may have implications for the sympathetic, cardiovascular, and renal changes associated with obesity...

..Thus, when PPARgamma activity in muscle is absent or reduced, there will be decreased fatty acid disposal leading to diminished energy utilization and ultimately adiposity...

..However, in any case, excess superoxide production as an intrinsic property of mitochondria of insulin-sensitive tissues does not result from conditions mimicking the pathophysiology of pre- or early diabetes...

..We aimed to investigate the association between risperidone-induced weight gain, leptin concentration, and the leptin gene (LEP) -2548G/A variants in youths...

..Moreover, concurrent leptin does not enhance catecholamine responses to insulin in rats exposed to antecedent hypoglycemia...

....

....

..Mitoquinol blocks ROS from reverse electron transport but increases superoxide production derived from forward transport. These effects likely occur at one or more Q binding sites in complex I...

..Prolonged use of continuous glucose monitoring was safe in the subjects studied, and is the first method clinically available to monitor glucose control over prolonged periods in individuals with diabetes...

..But, this is only achieved only at a higher body mass and, therefore, may be adaptive rather than preventative. Neither obesity-prone nor resistant mice respond to HF feeding by expressing more UCP1 in ectopic BAT within muscle tissue...

..If leptin resistance is selective in obese humans, then leptin could contribute to sympathetic overactivity and its adverse consequences in human obesity...

..UCP2-mediated H(+) conduction was not GDP sensitive. These data suggest that the UCP homologue, UCP2, mediates the proton leak in mitochondria of a mammalian cell wherein UCP2 is the native subtype...

..CONCLUSIONS: Obesity induced by 2-week ICV administration of NPY does not increase arterial pressure, perhaps indicating inhibition of sympathetic outflow that may oppose the pressor effect of adiposity...

..We propose that higher free fatty acid oxidation rates prevent accumulation of triglyceride in UCP2(-/-) islets, such accumulation being a phenomenon associated with lipotoxicity...

..In contrast, the increase in IBAT-SNA with leptin is not prevented by baroreflex activation, suggesting the recruitment of sympathetic fibers that serve thermogenic or metabolic and not circulatory functions...

..The effect depends on intact and functional leptin receptors because it occurs neither in rats with a leptin receptor defect nor in rats with acquired leptin resistance...

..This is mediated by one or more UCP subtype. 4. Altered mitochondrial coupling and consequent changes in mitochondrial ROS formation alter endothelial cell generation of nitric oxide. ..