Role of uncoupling protein 2 (UCP2) expression and 1α,25-(OH)2-D3 in modulating adipocyte apoptosis

Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1900, USA.
The FASEB Journal (Impact Factor: 5.48). 09/2004; 18(12):1430-2. DOI: 10.1096/fj.04-1971fje
Source: PubMed

ABSTRACT We previously found that 1alpha, 25-dihydroxyvitamin D3 [1alpha, 25-(OH)2-D3] modulates adipocyte lipid metabolism via a Ca2+-dependent mechanism and inhibits adipocyte UCP2 expression, indicating that the anti-obesity effects of dietary calcium are mediated by suppression of 1alpha, 25-(OH)2-D3 levels. However, because UCP2 reduces mitochondrial potential, we have evaluated the roles of UCP2, mitochondrial uncoupling, and 1alpha, 25-(OH)2-D3 in adipocyte apoptosis. Overexpressing UCP2 in 3T3-L1 cells induced marked reductions in mitochondrial potential (Deltapsi) and ATP production (P<0.01), increases in the expression of caspases (P<0.05), and a decrease in Bcl-2/Bax expression ratio (P<0.01). Physiological doses of 1alpha, 25-(OH)2-D3 (0.1-10 nM) restored mitochondrial Deltapsi in LI-UCP2 cells and protected against UCP2 overexpression-induced apoptosis (P<0.01), whereas a high dose (100 nM) stimulated apoptosis in 3T3-L1 and L1-UCP2 cells (P<0.05). 1alpha, 25-(OH)2-D3 stimulated cytosolic Ca2+ dose-dependently in both 3T3-L1 and L1-UCP2 cells. However, physiological doses suppressed mitochondrial Ca2+ levels by approximately 50% whereas the high dose increased mitochondrial Ca2+ by 25% (P<0.05); this explains stimulation of apoptosis by the high dose of 1alpha, 25-(OH)2-D3. Using high-calcium diets to suppress 1alpha, 25-(OH)2-D3 stimulated adipose tissue apoptosis in aP2 transgenic mice (P<0.01), suggesting that increasing dietary calcium stimulates adipose apoptosis and thereby further contributes to an anti-obesity effect of dietary calcium.

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    • "Recent cell culture data from Sun and Zemel [15] indicated that calcitriol increased proinflammatory cytokine gene expression and protein secretion from adipocytes and macrophages, and this response was dependent on Ca 2+ i -provoked reactive oxygen species (ROS) generation. Coculture of both cell types increased gene expression and protein secretion of proinflammatory cytokines, which was further enhanced by calcitriol [15]. In vivo evidence for the potential antiinflammatory properties of high dietary calcium both with and without dairy was demonstrated in the aP2-agouti transgenic mouse model of obesity, in which a high Ca, nonfat dry milk protein-based diet reduced WAT inflammatory gene expression and circulating cytokines. "
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    ABSTRACT: Background. Research on dairy foods to enhance weight and fat loss when incorporated into a modest weight loss diet has had mixed results. Objective. A 15-week controlled feeding study to determine if dairy foods enhance central fat and weight loss when incorporated in a modest energy restricted diet of overweight and obese adults. Design. A 3-week run-in to establish energy needs; a 12-week 500 kcal/d energy reduction with 71 low-dairy-consuming overweight and obese adults randomly assigned to diets: ≤1 serving dairy/d (low dairy, LD) or ≤4 servings dairy/d (adequate dairy, AD). All foods were weighed and provided by the metabolic kitchen. Weight, fat, intra-abdominal adipose tissue (IAAT), subcutaneous adipose tissue (SAT) macrophage number, SAT inflammatory gene expression, and circulating cytokines were measured. Results. No diet differences were observed in weight, fat, or IAAT loss; nor SAT mRNA expression of inflammation, circulating cytokines, fasting lipids, glucose, or insulin. There was a significant increase (P = 0.02) in serum 25-hydroxyvitamin D in the AD group. Conclusion. Whether increased dairy intake during weight loss results in greater weight and fat loss for individuals with metabolic syndrome deserves investigation. Assessment of appetite, hunger, and satiety with followup on weight regain should be considered.
    Journal of obesity 09/2011; 2011:989657. DOI:10.1155/2011/989657
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    • "Calcitriol also acts by the adipocyte nuclear vitamin D receptor to inhibit the expression of uncoupling protein-2 [33] and thus increase energy efficiency. Calcitriol regulation of uncoupling protein-2 and intracellular calcium appears to exert an additional role in energy metabolism by affecting adipocyte apoptosis [34]. "
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    ABSTRACT: An inverse relation between dietary calcium and adiposity has been found in several epidemiologic studies. Recent evidence has also suggested that a calcium-rich diet may have beneficial effects on insulin resistance and dyslipidemia. This study aimed to evaluate the association of dietary calcium intake with global adiposity, abdominal obesity, and metabolic profile in hypertensive patients. In this cross-sectional study, 85 hypertensive patients 25 to 70 y old underwent clinical, dietary, anthropometric, and biochemical evaluations. Participants were stratified into the following two groups according to their usual dietary calcium intake: low calcium group (<800 mg/d) and high calcium group (≥800 mg/d). Fifty-seven participants (11 men and 46 women) were included in the final analyses. Subjects in the low calcium group compared with those in the high calcium group exhibited significantly higher levels of body mass index and percentage of body fat after adjustments for variables that could interfere with those adiposity parameters (P = 0.03 and 0.01, respectively). Patients in the high calcium group had a lower odds ratio for prevalent obesity than those in the low calcium group, even after controlling for potential confounders (P = 0.01). No significant differences were found in abdominal adiposity and metabolic profile between the two groups. Using data from all patients, an inverse and significant association was observed between dietary calcium intake and percentage of body fat, and it remained after controlling for confounders (P = 0.03). The findings of the present study suggest that, in hypertensive patients, higher dietary calcium intake could be associated with lower global adiposity.
    Nutrition 10/2010; 27(6):666-71. DOI:10.1016/j.nut.2010.07.012 · 3.05 Impact Factor
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    • "Recently, it has been shown that UCP-2 up-regulation may contribute to cell death by altering expression of Bcl-2 proteins, such as increasing levels of the pro-death protein BNIP3 (Bcl-2/ adenovirus E1B 19kDa-interacting protein 3) (Bodyak et al., 2007) and decreasing levels of the anti-apoptotic protein Bcl-2 (Sun et al., 2004). Bcl-2 is reduced in a number of conditions associated with cell apoptosis, including lipopolysaccharide (LPS)-mediated death of endothelial cells (Blocksom et al., 2004) and neuronal death following cerebral ischemia (Sasaki et al., 2006). "
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    ABSTRACT: Cyanide is a potent inhibitor of mitochondrial oxidative metabolism and produces mitochondria-mediated death of dopaminergic neurons and sublethal intoxications that are associated with a Parkinson-like syndrome. Cyanide toxicity is enhanced when mitochondrial uncoupling is stimulated following up-regulation of uncoupling protein-2 (UCP-2). In this study, the role of a pro-survival protein, Bcl-2, in cyanide-mediated cell death was determined in a rat dopaminergic immortalized mesencephalic cell line (N27 cells). Following pharmacological up-regulation of UCP-2 by treatment with Wy14,643, cyanide reduced cellular Bcl-2 expression by increasing proteasomal degradation of the protein. The increased turnover of Bcl-2 was mediated by an increase of oxidative stress following UCP-2 up-regulation. The oxidative stress involved depletion of mitochondrial glutathione (mtGSH) and increased H2O2 generation. Repletion of mtGSH by loading cells with glutathione ethyl ester reduced H2O2 generation and in turn blocked the cyanide-induced decrease of Bcl-2. To determine if UCP-2 mediated the response, RNAi knock down was conducted. The RNAi decreased cyanide-induced depletion of mtGSH, reduced H2O2 accumulation, and inhibited down-regulation of Bcl-2, thus blocking cell death. To confirm the role of Bcl-2 down-regulation in the cell death, it was shown that over-expression of Bcl-2 by cDNA transfection attenuated the enhancement of cyanide toxicity after UCP-2 up-regulation. It was concluded that UCP-2 up-regulation sensitizes cells to cyanide by increasing cellular oxidative stress, leading to an increase of Bcl-2 degradation. Then the reduced Bcl-2 levels sensitize the cells to cyanide-mediated cell death.
    Toxicology and Applied Pharmacology 05/2009; 238(1):11-9. DOI:10.1016/j.taap.2009.03.020 · 3.63 Impact Factor
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