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 proprotein convertases (PCs) are responsible for the endoproteolytic processing of various protein precursors (e.g., growth factors, receptors, adhesion molecules, and matrix metalloproteinases) implicated in several diseases such as obesity, diabetes, atherosclerosis, cancer, and Alzheimer disease. The potential clinical and pharmacological role of the PCs has fostered the development of various PC-inhibitors. In this review we summarized the recent findings on PCs inhibitors, their mode of actions and potential use in the therapy of various diseases.
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PMID:Potential opportunity in the development of new therapeutic agents based on endogenous and exogenous inhibitors of the proprotein convertases. 1701 76

There is growing evidence that obesity is linked to adverse neurocognitive outcome, including reduced cognitive functioning and Alzheimer disease. However, no study to date has determined whether the relationship between body mass index (BMI) and cognitive performance varies as a function of age. We examined attention and executive function in a cross-section of 408 healthy persons across the adult life span (20-82 years). Bivariate correlation showed that BMI was inversely related to performance on all cognitive tests. After controlling for possible confounding factors, overweight and obese adults (BMI > 25) exhibited poorer executive function test performance than normal weight adults (BMI, 18.5-24.9). No differences emerged in attention test performance, and there was no evidence of a BMI x age interaction for either cognitive domain. These results provide further evidence for the relationship between elevated BMI and reduced cognitive performance and suggest that this relationship does not vary with age. Further research is needed to identify the etiology of these deficits and whether they resolve after weight loss.
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PMID:Elevated body mass index is associated with executive dysfunction in otherwise healthy adults. 1714 83

Adipose tissue is the largest endocrine gland in the body, yet only recently has its role in neurodegenerative disease been considered. Prospective population level evidence has emerged to show that both obesity and overweight, is associated with an increased risk of all cause dementia, Alzheimer's disease (AD), and underlying neurodegenerative changes. Weight loss in late life however is associated with dementia, and those categorized as underweight are also at a greater risk of dementia. Given the current epidemic of obesity, and the expected age-related increase in dementia incidence, even a small association between these two diseases has far reaching public health implications. However, due to the effects of both AD-associated weight loss and age-related changes in body composition, there are methodological challenges in appropriately evaluating obesity as a risk factor for developing dementia. There is a need to take a 'life course approach' and to consider the role of risk factors prior to the onset of old age. Our work has shown that both obesity and overweight, as measured by body mass index and skinfold thickness, in middle-age are strongly associated with an increased risk of all cause dementia, Alzheimer disease & Vascular dementia, independent of the development of diabetes and cardiovascular-related morbidities. There is also value in assessing regional body shape distributions of adiposity, particular the role of abdominal obesity. Mechanistic pathways such as adipocyte secreted proteins and hormones, and inflammatory cytokines could explain the association between obesity and increased risk of dementia.
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PMID:The epidemiology of adiposity and dementia. 1743 Feb 33

Insulin modulates cognition and other aspects of normal brain function. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. In addition, insulin resistance increases the risk of age-related memory impairment and Alzheimer's disease. Possible mechanisms through which these risks are increased include the effects of peripheral hyperinsulinemia on memory, CNS inflammation, and regulation of the beta-amyloid peptide. We have shown that raising plasma insulin in humans to levels that characterize patients with insulin resistance increases the levels of Abeta and inflammatory agents in brain. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit a subset of adults with age-related memory impairment and AD.
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PMID:Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment. 1743 Feb 39

Amylin (islet amyloid peptide) plays a critical role in islet amyloidosis and in the development of beta-cell dysfunction in patients with diabetes; however, the involvement of amylin in renal amyloidosis has not been studied. For this reason, we surveyed 149 patients with biopsy-proven diabetic nephropathy (DN). The results were compared to 95 renal disease control patients, which included membranoproliferative glomerulonephritis, light-chain deposition, IgA nephropathy, and obesity-related glomerulopathy (ORG). Seventy-two of the 149 patients with DN showed amylin deposition in their renal tissue. Amylin was mainly distributed in the expanded mesangial area, Kimmelstiel-Wilson nodules, Bowman's capsule, and in blood vessels. The frequencies of mesangial proliferation, glomerular nodule lesions, and glomerular sclerosis were higher in DN patients with amylin deposits. Furthermore, the tubular interstitial lesions were more severe in these patients. Of the 95 disease-control patients, four with ORG were positive for renal amylin deposits. Our study has found renal amylin deposition in patients with DN and that the deposition was associated with disease severity. We suggest that strict metabolic control and reversing insulin resistance in patients with diabetes may blunt the process of amylin deposition in the kidney and possibly protect renal function in these patients.
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PMID:Amylin deposition in the kidney of patients with diabetic nephropathy. 1749 60

The number of people over the age of 60 years with lifelong developmental delays is predicted to double by 2030. Down syndrome (DS) is the most frequent chromosomal cause of developmental delays. As the life expectancy of people with DS increases, changes in body function and structure secondary to aging have the potential to lead to activity limitations and participation restrictions for this population. The purpose of this update is to: (1) provide an overview of the common body function and structure changes that occur in adults with DS as they age (thyroid dysfunction, cardiovascular disorders, obesity, musculoskeletal disorders, Alzheimer disease, depression) and (2) apply current research on exercise to the prevention of activity limitations and participation restrictions. As individuals with DS age, a shift in emphasis from disability prevention to the prevention of conditions that lead to activity and participation limitations must occur. Exercise programs appear to have potential to positively affect the overall health of adults with DS, thereby increasing the quality of life and years of healthy life for these individuals.
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PMID:Aging and Down syndrome: implications for physical therapy. 1771 35

Compelling evidence indicates that excess consumption of sugar-sweetened beverages plays an important role in the epidemic of obesity, a major risk factor for type 2 diabetes mellitus. Type 2 diabetes mellitus has been associated with a higher incidence of Alzheimer disease (AD). High fat diets promote AD-like pathology in mice. It is not known whether consumption of excess sugar as in calorically sweetened beverages with an otherwise normal diet affects the development of AD. In the present study, we provided 10% sucrose-sweetened water to a transgenic mouse model of AD with a normal rodent diet. Compared with the control mice with no sucrose added in the water, the sucrose group gained more body weight and developed glucose intolerance, hyperinsulinemia, and hypercholesterolemia. These metabolic changes were associated with the exacerbation of memory impairment and a 2-3-fold increase in insoluble amyloid-beta protein levels and deposition in the brain. We further showed that the levels of expression and secretase-cleaved products of amyloid-beta precursor protein were not affected by sucrose intake. The steady-state levels of insulin-degrading enzyme did not change significantly, whereas there was a 2.5-fold increase in brain apoE levels. Therefore, we concluded that the up-regulation of apoE accelerated the aggregation of Abeta, resulting in the exacerbation of cerebral amyloidosis in sucrose-treated mice. These data underscore the potential role of dietary sugar in the pathogenesis of AD and suggest that controlling the consumption of sugar-sweetened beverages may be an effective way to curtail the risk of developing AD.
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PMID:Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. 1794 1

The signaling adapter p62 plays a coordinating role in mediating phosphorylation and ubiquitin-dependent trafficking of interacting proteins. However, there is little known about the physiologic role of this protein in brain. Here, we report age-dependent constitutive activation of glycogen synthase kinase 3beta, protein kinase B, mitogen-activated protein kinase, and c-Jun-N-terminal kinase in adult p62(-/-) mice resulting in hyperphosphorylated tau, neurofibrillary tangles, and neurodegeneration. Biochemical fractionation of p62(-/-) brain led to recovery of aggregated K63-ubiquitinated tau. Loss of p62 was manifested by increased anxiety, depression, loss of working memory, and reduced serum brain-derived neurotrophic factor levels. Our findings reveal a novel role for p62 as a chaperone that regulates tau solubility thereby preventing tau aggregation. This study provides a clear demonstration of an Alzheimer-like phenotype in a mouse model in the absence of expression of human genes carrying mutations in amyloid-beta protein precursor, presenilin, or tau. Thus, these findings provide new insight into manifestation of sporadic Alzheimer disease and the impact of obesity.
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PMID:Genetic inactivation of p62 leads to accumulation of hyperphosphorylated tau and neurodegeneration. 1834 6

The aim of this study was to determine whether amyloid precursor protein (APP) is expressed in human adipose tissue, dysregulated in obesity, and related to insulin resistance and inflammation. APP expression was examined by microarray expression profiling of subcutaneous abdominal adipocytes (SAC) and cultured preadipocytes from obese and nonobese subjects. Quantitative real-time PCR (QPCR) was performed to confirm differences in APP expression in SAC and to compare APP expression levels in adipose tissue, adipocytes, and stromal vascular cells (SVCs) from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) specimens. Adipose tissue samples were also examined by western blot and immunofluorescence confocal microscopy. Microarray studies demonstrated that APP mRNA expression levels were higher in SAC (approximately 2.5-fold) and preadipocytes (approximately 1.4) from obese subjects. Real-time PCR confirmed increased APP expression in SAC in a separate group of obese compared with nonobese subjects (P=0.02). APP expression correlated to in vivo indices of insulin resistance independently of BMI and with the expression of proinflammatory genes, such as monocyte chemoattractant protein-1 (MCP-1) (R=0.62, P=0.004), macrophage inflammatory protein-1alpha (MIP-1alpha) (R=0.60, P=0.005), and interleukin-6 (IL-6) (R=0.71, P=0.0005). Full-length APP protein was detected in adipocytes by western blotting and APP and its cleavage peptides, Abeta40 and Abeta42, were observed in SAT and VAT by immunofluorescence confocal microscopy. In summary, APP is highly expressed in adipose tissue, upregulated in obesity, and expression levels correlate with insulin resistance and adipocyte cytokine expression levels. These data suggest a possible role for APP and/or Abeta in the development of obesity-related insulin resistance and adipose tissue inflammation.
Obesity (Silver Spring) 2008 Jul
PMID:Amyloid precursor protein expression is upregulated in adipocytes in obesity. 1848 77

In recent years a rapidly increasing number of studies has focused on the relationship between dementia and metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. Etiological heterogeneity and comorbidity pose challenges for determining relationships among metabolic disorders. The independent and interactive effects of brain vascular injury and classic pathological agents such as beta-amyloid have also proved difficult to distinguish in human patients, blurring the lines between Alzheimer disease and vascular dementia. This review highlights recent work aimed at identifying convergent mechanisms such as insulin resistance that may underlie comorbid metabolic disorders and thereby increase dementia risk. Identification of such convergent factors will not only provide important insight into the causes and interdependencies of late-life dementias but will also inspire novel strategies for treating and preventing these disorders.
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PMID:The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. 1927 47


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