Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of nanomolar concentrations of guanine, but not adenine, nucleotides to inhibit specific 125I-Bolton-Hunter CCK binding to ligated rat vagus nerve demonstrated that vagal CCK binding sites were linked to G-proteins during axonal transport. The GTP analogue, GTP[S], reduced specific binding to both anterogradely and retrogradely transported binding sites by more than 90% at 1 microM. Transport of these putative receptor-G-protein complexes was examined under conditions of food deprivation or physiological hyperphagia induced by either lactation or genetic obesity. None of the physiological or imposed manipulations of food intake had any effect on the axonal transport of CCK binding sites. Transection of the cervical vagus resulted in an accumulation of binding sites at the lesion site that was indistinguishable from that seen following ligation for the same period.
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PMID:G-protein coupling of vagal CCK binding sites and comparisons of transport rates. 768 78

Although simultaneous pancreas and kidney transplantation (SPK) achieves normoglycemia and correction of uremia in type I diabetic patients with renal failure, little data are available on long-term outcome and clinical determinants of recovery of peripheral neuropathy. In this prospective study, 219 electrophysiological studies using a standardized protocol were performed before and up to 8 years after SPK in 44 patients. Nine control diabetic recipients with functioning kidney but nonfunctioning pancreas transplants were studied on 35 occasions. Patients were 38.5+/-7.9 years old (mean+/-SD) with pretransplant diabetes present for 25.2+/-7.6 years. Significant polyneuropathy (total nerve conduction scores [NCS] <-1.0) was present in 89% before transplantation, which correlated with body weight (r=0.628, P<0.001). Two distinct patterns of neurological recovery were observed after SPK. Conduction velocity (CV) improved in a biphasic pattern, with a rapid initial recovery followed by subsequent stabilization. In contrast, the recovery of nerve amplitude was monophasic, and continued to improve for up to 8 years. Initial improvement in NCS was primarily due to an increase in CV (P=0.002 vs. baseline), and was best in shorter and younger patients. Recovery of total NCS at 6 months after SPK, assessed by multivariate analysis, was least in obese recipients and when performed in patients who had started dialysis before SPK, and was associated with lower transplant kidney isotopic glomerular filtration rate and HLA mismatch (P<0.05 to 0.001). Subsequent improvement was associated with less severe initial neuropathy, smaller body weight, and longer duration of diabetes (P<0.01 to 0.001). Fasting hyperinsulinemia was associated with impairment of initial recovery and subsequent NCS after SPK, but was worse in the control group. Recovery of nerve action potential amplitudes was predicted by better initial amplitudes and HLA mismatch, lower body weight, and the use of nifedipine (P<0.05 to 0.001). Nifedipine was used for hypertension in 33% of SPK and was associated with better CV and amplitudes, particularly in the upper limbs, where there was less neuropathy. The use of angiotensin-converting enzyme inhibitors also appeared beneficial, but this was confined to the lower limbs. SPK resulted in a gradual, sustained, and late improvement in nerve action potential amplitudes, consistent with axonal regeneration and partial reversal of diabetic neuropathy. These data suggest that early transplantation of uremic diabetic patients before onset of severe neuropathy, minimizing obesity and optimizing renal transplant function, maximizes neurological recovery after SPK. Furthermore, the preliminary data support randomized clinical trials for evaluation of nifedipine and angiotensin-converting enzyme inhibitors in diabetic neuropathy.
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PMID:Diabetic neuropathy after pancreas transplantation: determinants of recovery. 908 22

Energy dissipating mechanisms and their regulatory components represent key elements of metabolism and may offer novel targets in the treatment of metabolic disorders, such as obesity and diabetes. Recent studies have shown that a mitochondrial uncoupling protein (UCP2), which uncouples mitochondrial oxidation from phosphorylation, is expressed in the rodent brain by neurons that are known to regulate autonomic, metabolic, and endocrine processes. To help establish the relevance of these rodent data to primate physiology, we now examined UCP2 messenger RNA and peptide expressions in the brain and pituitary gland of nonhuman primates. In situ hybridization histochemistry showed that UCP2 messenger RNA is expressed in the paraventricular, supraoptic, suprachiasmatic, and arcuate nuclei of the primate hypothalamus and also in the anterior lobe of the pituitary gland. Immunocytochemistry revealed abundant UCP2 expression in cell bodies and axonal processes in the aforementioned nuclei as well as in other hypothalamic and brain stem regions and all parts of the pituitary gland. In the hypothalamus, UCP2 was coexpressed with neuropeptide Y, CRH, oxytocin, and vasopressin. In the pituitary, vasopressin and oxytocin-producing axonal processes in the posterior lobe and POMC cells in the intermediate and anterior lobes expressed UCP2. On the other hand, none of the GH-producing cells of the anterior pituitary was found to produce UCP2. The abundance and distribution pattern of UCP2 in the primate brain and pituitary suggest that this protein is evolutionary conserved and may relate to central autonomic, endocrine and metabolic regulation.
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PMID:Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. 1108 57

Strain-specific differences contributing to spontaneous age-related peripheral nerve changes were examined in three different strains of 100-week-old female mice housed under the same conditions over the same period: inbred C57BL and C3H strains, and the hybrid B6C3F1 strain. A lower incidence of obesity and significantly lower body weight, grasping power of fore- and hind-limbs, blood lipid level, tail-flick latency and motor nerve conduction velocity were observed in C57BL mice; significantly lower body temperature, blood glucose and HbA1c levels were observed in C3H mice. Histological examination conducted on isolated sciatic nerves and brachial plexuses revealed peripheral nerve lesions, characterized by axonal degeneration and remyelination, in all strains. Although the extent of histopathologic change in nerve fibers was similar in quality to those observed in all three mouse strains, the incidence and severity of nerve lesions in B6C3F1 and C3H mice were significantly greater than those observed in C57BL mice.
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PMID:A parallel comparison of age-related peripheral nerve changes in three different strains of mice. 1110 56

Small lesions centered in the posterodorsal region of the medial amygdala resulted in excessive weight gains in female rats. Unilateral lesions were nearly as effective as bilateral lesions in the first 48 h after surgery (+21 to +32 g). Assessment of lesion damage was done by both qualitative evaluation and by a quantitative grid-point counting method. The critical sites for weight gain were the intra-amygdaloid bed nucleus of the stria terminalis and the posterodorsal medial amygdaloid nucleus. Incidental damage to the overlying globus pallidus was negatively related to weight gain. The cupric silver method for demonstrating axonal degeneration was applied to brains with obesity-inducing lesions. A dense pattern of degenerating terminals was found in the lateral septum, amygdala, ventral striatum, and ventromedial hypothalamus. Degeneration in the paraventricular nucleus of the hypothalamus was scarce or absent. Small retrograde tracer injections made in either the intra-amygdaloid bed nucleus of the stria terminalis or in the posterodorsal medial amygdaloid nucleus labeled cells in the amygdala, lateral septum, and hypothalamus, reciprocating the anterograde projections from the amygdala to these areas. The data suggest that subdivisions of the posterodorsal amygdala participate in the regulation of feeding in a manner that is similar to the better-known role of this part of the brain in mediating reproductive behavior. Although topographical differences may exist within the amygdaloid and hypothalamic subdivisions regulating these two sexually dimorphic behaviors, the relays engaged by feeding-related connections and those related to reproduction are remarkably parallel.
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PMID:Obesity-inducing amygdala lesions: examination of anterograde degeneration and retrograde transport. 1243 73

Necdin and Magel2 are related proteins inactivated in Prader-Willi syndrome (PWS), a sporadic chromosomal deletion disorder. We demonstrate that necdin and Magel2 bind to and prevent proteasomal degradation of Fez1, a fasciculation and elongation protein implicated in axonal outgrowth and kinesin-mediated transport, and also bind to the Bardet-Biedl syndrome (BBS) protein BBS4 in co-transfected cells. The interactions among necdin, Magel2, Fez1 and BBS4 occur at or near centrosomes. Centrosomal or pericentriolar dysfunction has previously been implicated in BBS and may also be important in the features of PWS that overlap with BBS, such as learning disabilities, hypogonadism and obesity. Morphological abnormalities in axonal outgrowth and fasciculation manifest in several regions of the nervous system in necdin null mouse embryos, including axons of sympathetic, retinal ganglion cell, serotonergic and catecholaminergic neurons. These data demonstrate that necdin mediates intracellular processes essential for neurite outgrowth and that loss of necdin impinges on axonal outgrowth. We further suggest that loss of necdin contributes to the neurological phenotype of PWS, and raise the possibility that co-deletion of necdin and the related protein Magel2 may explain the lack of single gene mutations in PWS.
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PMID:Essential role for the Prader-Willi syndrome protein necdin in axonal outgrowth. 1564 43

Lesions of the amygdala have long been known to produce hyperphagia and obesity in cats, dogs, and monkeys, but only recently have studies with rats determined that the effective site is the posterodorsal amygdala (PDA)-the posterodorsal medial amygdaloid nucleus and the intra-amygdaloid bed nucleus of the stria terminalis. There is a sex difference; female rats with PDA lesions display greater weight gain than male rats. In the brains of female rats with obesity-inducing PDA lesions, there is a dense pattern of axonal degeneration in the capsule of the ventromedial hypothalamus (VMH) and other targets of the stria terminalis. Transections of the dorsal component of the stria terminalis also result in hyperphagia and obesity in female rats. Similar to rats with VMH lesions, rats with PDA lesions are hyperinsulinemic during food restriction and greatly prefer high-carbohydrate diets. The PDA is also a critical site for some aspects of rodent sexual behavior, particularly those that depend on olfaction, and the pattern of degeneration observed after obesity-inducing PDA lesions is remarkably parallel to the circuit that has been proposed to mediate sexual behavior. Medial amygdaloid lesions disrupt the normal feeding pattern and result in impaired responses to caloric challenges, and there is evidence that these behavioral changes are also due to a disruption of olfactory input. With its input from the olfactory bulbs and connections to the VMH, the PDA may be a nodal point at which olfactory and neuroendocrine stimuli are integrated to affect feeding behavior.
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PMID:Amygdaloid lesion-induced obesity: relation to sexual behavior, olfaction, and the ventromedial hypothalamus. 1677 67

Much of our understanding of the effects of diabetes on the peripheral nervous system is derived from models induced by streptozotocin in which hyperglycemia is rapidly caused by pancreatic beta-cell destruction. Here, we have quantified sensory impairments over time in leptin receptor (lepr)-null mutant -/- mice, a type 2 model of diabetes in which the absence of leptin receptor signaling leads to obesity and chronic hyperglycemia by 4 weeks of age. To assess these mice as a model for peripheral neuropathy, we quantified the responsiveness of lepr -/- mice to mechanical, thermal, and chemogenic stimuli, as well as epidermal and dermal innervation of the hind paw. Compared with wild-type +/+ and heterozygous +/- mice, lepr -/- mice displayed reduced sensitivity to mechanical stimuli by 6 weeks of age, and however, responses to noxious heat were normal. Lepr -/- mice also devoted less activity to their injected paw during the second phase following formalin administration. However, epidermal and dermal innervation of lepr -/- mice was not different from that of lepr +/+ and +/- mice even after 10 weeks of hyperglycemia, suggesting that cutaneous innervation is resistant to chronic hyperglycemia in these mice. These results suggest that certain rodent nocifensive behaviors may be linked to the abundance of cutaneous innervation, while others are not. Finally, these results reveal that the lepr -/- mice may not be useful to study neuropathy associated with distal axonal degeneration but may be better suited for studies of hyperglycemia-induced sensory neuron dysfunction without distal nerve loss.
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PMID:Selective changes in nocifensive behavior despite normal cutaneous axon innervation in leptin receptor-null mutant (db/db) mice. 1804 35

The number one cause of mortality in the US is cardiovascular related disease. Future predictions do not see a reduction in this rate especially with the continued rise in obesity [P. Poirier, et al., Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss, Arterioscler Thromb Vasc Biol. 26(5), (2006) 968-976.; K. Obunai, S. Jani, G.D. Dangas, Cardiovascular morbidity and mortality of the metabolic syndrome, Med.Clin. North Am., 91(6), (2007) 1169-1184]. Even so, potential molecular therapeutic targets for cardiac gene delivery are in no short supply thanks to continuing advances in molecular cardiology. However, efficient and safe delivery remains a bottleneck in clinical gene therapy [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Viral vectors are looked upon favorably for their high transduction efficiency, although their ability to elicit toxic immune responses remains [C.F. McTiernan, et al., Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts, Gene Ther, 14(23), (2007) 1613-1622]. However, this high transduction does not necessarily translate into improved efficacy [X. Hao, et al., Myocardial angiogenesis after plasmid or adenoviral VEGF-A(165) gene transfer in rat myocardial infarction model, Cardiovasc Res., 73(3), (2007) 481-487]. Naked DNA remains the preferred method of DNA delivery to cardiac myocardium and has been explored extensively in clinical trials. The results from these trials have demonstrated efficacy in regard to secondary end-points of reduced symptomatology and perfusion, but have failed to establish significant angiogenesis or an increase in myocardial function [P.B. Shah, D.W. Losordo, Non-viral vectors for gene therapy: clinical trials in cardiovascular disease, Adv Genet, 54, (2005) 339-361]. This may be due in part to reduced transfection efficiency but can also be attributed to use of suboptimal candidate genes. Currently, polymeric non-viral gene delivery to cardiac myocardium remains underrepresented. In the past decade several advances in non-viral vector development has demonstrated increased transfection efficiency [O.J. Muller, H.A. Katus, R. Bekeredjian, Targeting the heart with gene therapy-optimized gene delivery methods, Cardiovasc Res, 73(3), (2007) 453-462]. Of these polymers, those that employ lipid modifications to improve transfection or target cardiovascular tissues have proven themselves to be extremely beneficial. Water-soluble lipopolymer (WSLP) consists of a low molecular weight branched PEI (1800) and cholesterol. The cholesterol moiety adds extra condensation by forming stable micellular complexes and was later employed for myocardial gene therapy to exploit the high expression of lipoprotein lipase found within cardiac tissue. Use of WSLP to deliver hypoxia-responsive driven expression of hVEGF to ischemic rabbit myocardium has proven to provide for even better expression in cardiovascular cells than Terplex and has demonstrated a significant reduction in infarct size (13+/-4%, p<0.001) over constitutive VEGF expression (32+/-7%, p=0.007) and sham-injected controls (48+/-7%). A significant reduction in apoptotic values and an increase in capillary growth were also seen in surrounding tissue. Recently, investigations have begun using bioreducible polymers made of poly(amido polyethylenimines) (SS-PAEI). SS-PAEIs breakdown within the cytoplasm through inherent redox mechanisms and provide for high transfection efficiencies (upwards to 60% in cardiovascular cell types) with little to no demonstrable toxicity. In vivo transfections in normoxic and hypoxic rabbit myocardium have proven to exceed those results of WSLP transfections by 2-5 fold [L.V. Christensen, et al., Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery, J Control Release, 118(2), (2007) 254-261]. This new breed of polymer(s) may allow for decreased doses and use of new molecular mechanisms not previously available due to low transfection efficiencies. Little development has been seen in the use of new gene agents for treatment of myocardial ischemia and infarction. Current treatment consists of using mitogenic factors, described decades earlier, alone or in combination to spur angiogenesis or modulating intracellular Ca2+ homeostasis through SERCA2a but to date, failed to demonstrate clinical efficacy. Recent data suggests that axonal guidance cues also act on vasculature neo-genesis and provide a new means of investigation for treatment.
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PMID:Novel polymer carriers and gene constructs for treatment of myocardial ischemia and infarction. 1866 30

The role of insulin pathways in olfaction is of significant interest with the widespread pathology of diabetes mellitus and its associated metabolic and neuronal comorbidities. The insulin receptor (IR) kinase is expressed at high levels in the olfactory bulb, in which it suppresses a dominant Shaker ion channel (Kv1.3) via tyrosine phosphorylation of critical N- and C-terminal residues. We optimized a 7 d intranasal insulin delivery (IND) in awake mice to ascertain the biochemical and behavioral effects of insulin to this brain region, given that nasal sprays for insulin have been marketed notwithstanding our knowledge of the role of Kv1.3 in olfaction, metabolism, and axon targeting. IND evoked robust phosphorylation of Kv1.3, as well as increased channel protein-protein interactions with IR and postsynaptic density 95. IND-treated mice had an increased short- and long-term object memory recognition, increased anxiolytic behavior, and an increased odor discrimination using an odor habituation protocol but only moderate change in odor threshold using a two-choice paradigm. Unlike Kv1.3 gene-targeted deletion that alters metabolism, adiposity, and axonal targeting to defined olfactory glomeruli, suppression of Kv1.3 via IND had no effect on body weight nor the size and number of M72 glomeruli or the route of its sensory axon projections. There was no evidence of altered expression of sensory neurons in the epithelium. In mice made prediabetic via diet-induced obesity, IND was no longer effective in increasing long-term object memory recognition nor increasing anxiolytic behavior, suggesting state dependency or a degree of insulin resistance related to these behaviors.
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PMID:Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. 1945 42


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