Mutant Amyloid Precursor Protein Differentially Alters Adipose Biology under Obesogenic and Non-Obesogenic Conditions

Pennington Biomedical Research Center/LSU System, Baton Rouge, Louisiana, United States of America.
PLoS ONE (Impact Factor: 3.53). 08/2012; 7(8):e43193. DOI: 10.1371/journal.pone.0043193
Source: PubMed

ABSTRACT Mutations in amyloid precursor protein (APP) have been most intensely studied in brain tissue for their link to Alzheimer's disease (AD) pathology. However, APP is highly expressed in a variety of tissues including adipose tissue, where APP is also known to exhibit increased expression in response to obesity. In our current study, we analyzed the effects of mutant APP (E693Q, D694N, K670N/M671L) expression toward multiple aspects of adipose tissue homeostasis. These data reveal significant hypoleptinemia, decreased adiposity, and reduced adipocyte size in response to mutant APP, and this was fully reversed upon high fat diet administration. Additionally, mutant APP was observed to significantly exacerbate insulin resistance, triglyceride elevations, and macrophage infiltration of adipose tissue in response to a high fat diet. Taken together, these data have significant implications for linking mutant APP expression to adipose tissue dysfunction and global changes in endocrine and metabolic function under both obesogenic and non-obesogenic conditions.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The global epidemic in obesity and diabetes has affected individuals in both the developing and developed world with the global death rate (63%) related to chronic diseases with 35% attributed to cardiovascular disease and stroke, 21 % to cancer and 12 % to chronic respiratory disease. The interest in connections between the global stroke epidemic, dementia and Alzheimer’s disease (AD) has increased with hypertension, smoking, diabetes, obesity, poor diet, physical inactivity, atrial fibrillation, excessive alcohol consumption, abnormal lipid profile and psychosocial stress/depression implicated in their pathogenesis. The connection between stroke and AD is possibly related to the low adiponectin and high density lipoprotein (HDL) cholesterol levels that are found in hypertensive, obese, diabetic and AD individuals. In obesity adipocyte dysfunction may be related to the down regulation of the AD gene Sirtuin 1, overexpression of the amyloid precursor protein (APP) and mitochondrial apoptosis with relevance to the renin-angiotensin system (RAS) that is associated with accelerated aging, NAFLD, stroke and AD. The unresolved finding of low plasma HDL and adiponectin in the metabolic syndrome may involve the stress hormone angiotensin II (Ang II) with vascular disturbances. Increased levels of adipocyte Ang II are possibly linked to the low plasma HDL contents in stroke and AD individuals. In obese and diabetic individuals the release of stress factors and diet control the activation of the RAS with increased levels of Ang II that are possibly implicated in the dyslipidemia associated with hypertension, cardiovascular disease, stroke and AD related dementia.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to investigate proliferator-activated receptor (PPARγ), fatty acid synthase (FAS) and hormone-sensitive lipase (HSL) mRNA and protein expression in fat tails of Tan sheep. Rams from different developmental stages (aged 3, 6, 9, 12, 15 and 18 months) were selected, and their tail measurements including length (L), width (W) and girth (G) were recorded. The mRNA and protein expressions of PPARγ, FAS and HSL were examined by quantitative real-time polymerase chain reaction (PCR) and Western blot.
    Electronic Journal of Biotechnology 02/2015; 43(2). DOI:10.1016/j.ejbt.2015.01.004 · 0.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this work, we report a series of new 4-oxo-1,4-dihydro-quinoline-3-carboxamide derivatives as β-secretase (BACE-1) inhibitors. Supported by docking study, a small library of derivatives were designed, synthesized and biologically evaluated in vitro. The studies revealed that the most potent analog 14e (IC50 = 1.89 μM) with low cellular cytotoxicity and high predicted blood brain barrier permeability, could serve as a good structure for further modification.
    European Journal of Medicinal Chemistry 04/2014; 79C:413-421. DOI:10.1016/j.ejmech.2014.04.025 · 3.43 Impact Factor