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: 5.04).
09/2004; 18(12):1430-2. DOI: 10.1096/fj.04-1971fje
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.
Available from: John William Newman
- "In vivo evidence has shown increased dietary calcium, both with and without dairy, diminished inflammation and oxidative stress in genetically-modified obese animals, with the interpretive caveat that adiposity was also reduced under these conditions . Increased dietary calcium dampens circulating calcitriol, and calcitriol has been shown to activate pro-inflammatory pathways by inducing reactive oxygen species generation and cytokine release in adipocytes and macrophages [13,14]. However, anti-inflammatory actions of calcitriol have also been reported in humans , and serum calcitriol has been reported to be significantly lower in obese verses non-obese human subjects . "
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Diets rich in dairy and/or calcium (Ca) have been associated with reductions in adiposity and inflammation, but the mechanisms underlying this remain to be fully elucidated. Oxylipins and endocannabinoids are bioactive lipids, which influence energy homeostasis, adipose function, insulin signaling, and inflammation. Our objective was to determine if these metabolites associate with metabolic and inflammatory phenotypes stemming from dietary Ca and dairy in diet induced obese mice.
In one study, C57BL6/J mice were fed high fat diets (45% energy) with varying dietary matrices for 12 weeks: soy protein and Ca adequate (0.5%; CONTROL), soy protein and high Ca (1.5%; HighCa), or nonfat-dry-milk based high Ca (NFDM). In a second study, mice were pre-fattened for 12 weeks on the CONTROL high fat diet, and then fed one of three high fat diets for an additional 8 weeks: CONTROL, HighCa, or NFDM. In both studies, adiposity and associated metabolic and inflammatory outcomes were measured and a targeted lipidomics analysis was performed on plasma collected during the post-absorptive condition.
As reported previously, mice fed NFDM had less body fat and reduced mRNA markers of adipose inflammation (p < 0.05) than CONTROL mice despite greater cumulative energy intake. Moreover, NFDM fed mice lipid mediator profiles were distinct from CONTROL and HighCa mice. NFDM fed mice showed elevated plasma monoacylglycerols (6 – 46% increase from CONTROL), including 2-arachidonoylglycerol (2-AG), and reduced fatty acid diols (8-75% decrease from CONTROL).
Differences in specific plasma lipid mediator profiles reflect the metabolic and inflammatory phenotypes seen in NFDM feeding.
Available from: Antje Bruckbauer
- "Dairy foods have been reported to have multiple effects on adipocyte and muscle metabolism and therefore play a significant role in modulating energy metabolism and obesity risk [7-9]. While some of these effects appear to be mediated by dietary calcium , recent evidence indicates that the high concentration of branched chain amino acids (BCAA) contribute to these effects. "
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ABSTRACT: Recent data from this laboratory suggest that components of dairy foods may serve as activators of SIRT1 (Silent Information Regulator Transcript 1), and thereby participate in regulation of glucose and lipid metabolism. In this study, an ex-vivo/in-vitro approach was used to examine the integrated effects of dairy diets on SIRT1 activation in two key target tissues (adipose and muscle tissue).
Serum from overweight and obese subjects fed low or high dairy diets for 28 days was added to culture medium (similar to conditioned media) to treat cultured adipocytes and muscle cells for 48 hours.
Treatment with high dairy group conditioned media resulted in 40% increased SIRT1 gene expression in both tissues (p < 0.01) and 13% increased enzyme activity in adipose tissue compared to baseline. This was associated with increased gene expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), cytochrome oxidase c subunit 7 (Cox 7), NADH dehydrogenase and uncoupling protein 2 (UCP2) in adipocytes as well as uncoupling protein 3 (UCP3), NRF1 and Cox 7 in muscle cells (p < 0.05). Further, direct incubation of physiological concentrations of leucine and its metabolites α-Ketoisocaproic acid (KIC) and β-hydroxy-methylbuteric acid (HMB) with recombinant human SIRT1 enzyme resulted in 30 to 50% increase of SIRT1 activity (p < 0.05).
These data indicate that dairy consumption leads to systemic effects, which may promote mitochondrial biogenesis in key target tissues such as muscle and adipose tissue both by direct activation of SIRT1 as well as by SIRT1-independent pathways.
Available from: Nancy L Keim
- "Recent cell culture data from Sun and Zemel  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 . 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.
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