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 (~2.5-fold) and preadipocytes (~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-1α (MIP-1α) (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, Aβ40 and Aβ42, 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 Aβ in the development of obesity-related insulin resistance and adipose tissue inflammation.
Background/Aims: Several studies have demonstrated that midlife obesity increases the risk for dementia and Alzheimer’s disease. Moreover, plasma 42-amino-acid amyloid-β (Aβ42) levels appear to correlate with BMI. We recently demonstrated that adipocyte amyloid precursor protein (APP) expression is upregulated in obesity and correlates with insulin resistance and adipose tissue inflammation. In this study, we aimed to investigate the relation between adipocyte APP expression and plasma Aβ peptide levels. Methods: We conducted a pilot study in which we measured adipocyte APP gene expression and the circulating plasma levels of Aβ40 in 10 obese individuals before and after a 6-month behaviorally based weight loss intervention. Subjects had an oral glucose tolerance test with measurement of insulin levels, Aβ40 levels measured by ELISA and transcript levels of APP in subcutaneous abdominal adipocytes measured by quantitative real-time PCR. Results: At baseline, adipocyte APP expression correlated significantly with plasma Aβ40 levels and with 2-hour insulin concentrations. Following the 6-month weight loss intervention, body weight and BMI decreased significantly. Fasting plasma concentrations of glucose and insulin were improved. Adipocyte APP expression was significantly decreased (p < 0.001) after weight loss. Changes in adipocyte APP expression correlated with changes in plasma Aβ40 levels (R = 0.74, p = 0.01) and changes in 2-hour insulin (R = 0.75, p = 0.01). Conclusion: The results of this pilot study suggest that increased circulating plasma levels of Aβ peptides in obesity may be due to increased adipocyte APP gene expression. While these results suggest a possible mechanism linking midlife obesity with the later development of Alzheimer’s disease, further research is necessary to elucidate the regulation and functional significance of APP in adipocytes.
The persistence of back pain following acute back “sprains” is a serious public health problem with poorly understood pathophysiology. The recent finding that human subjects with chronic low back pain (LBP) have increased thickness and decreased mobility of the thoracolumbar fascia measured with ultrasound suggest that the fasciae of the back may be involved in LBP pathophysiology. This study used a porcine model to test the hypothesis that similar ultrasound findings can be produced experimentally in a porcine model by combining a local injury of fascia with movement restriction using a “hobble” device linking one foot to a chest harness for 8 weeks. Ultrasound measurements of thoracolumbar fascia thickness and shear plane mobility (shear strain) during passive hip flexion were made at the 8 week time point on the non-intervention side (injury and/or hobble). Injury alone caused both an increase in fascia thickness (p = .007) and a decrease in fascia shear strain on the non-injured side (p = .027). Movement restriction alone did not change fascia thickness but did decrease shear strain on the non-hobble side (p = .024). The combination of injury plus movement restriction had additive effects on reducing fascia mobility with a 52% reduction in shear strain compared with controls and a 28% reduction compared to movement restriction alone. These results suggest that a back injury involving fascia, even when healed, can affect the relative mobility of fascia layers away from the injured area, especially when movement is also restricted.
The objectives of this study were to determine the local effects of transforming growth factor-beta1 (TGF-beta1) on mammary epithelial and stromal cell proliferation and expression of the TGF-beta1 responsive genes c-myc and fibronectin. A single slow-release plastic pellet containing 5 microg of TGF-beta1 and 20 mg of BSA was implanted in the parenchyma of the right rear quarter of the mammary gland of 9-mo-old prepubertal heifers. A control pellet containing 20 mg of BSA was implanted in the left rear quarter of each heifer. All heifers were treated with bromodeoxyuridine (BrdU) at 4, 12.5, and 22 h after the pellets were implanted to label proliferating cells. Two hours after the last BrdU injection, the animals were euthanatized, and their mammary glands were recovered. Proliferation of mammary stromal cells was significantly higher in TGF-beta1-treated quarters than in BSA-treated, control quarters (3.5 vs. 1.8% BrdU-positive cells). This result coincided with a lack of significant effect of TGF-beta1 on proliferation of mammary epithelial cells and apoptosis. By quantitative reverse transcriptase-polymerase chain reaction, we found that c-myc gene expression was unchanged after TGF-beta1 treatment, but fibronectin gene expression was increased 3-fold in TGF-beta1-treated quarters compared with BSA-treated, control quarters. Thus, we concluded that TGF-beta1 selectively acts on the stromal compartment of the bovine mammary gland by increasing cell proliferation and gene expression of the extracellular matrix protein fibronectin.
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