Effects of dairy consumption on SIRT1 and mitochondrial biogenesis in adipocytes and muscle cells

<p>Abstract</p> <p>Background</p> <p>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 <it>ex-vivo/in-vitro </it>approach was used to examine the integrated effects of dairy diets on SIRT1 activation in two key target tissues (adipose and muscle tissue).</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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).</p> <p>Conclusions</p> <p>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.</p

Leucine modulation of mitochondrial mass and oxygen consumption in skeletal muscle cells and adipocytes

<p>Abstract</p> <p>Background</p> <p>The effects of dairy on energy metabolism appear to be mediated, in part, by leucine and calcium which regulate both adipocyte and skeletal muscle energy metabolism. We recently demonstrated that leucine and calcitriol regulate fatty acid oxidation in skeletal muscle cells <it>in vitro</it>, with leucine promoting and calcitriol suppressing fatty acid oxidation. Moreover, leucine coordinately regulated adipocyte lipid metabolism to promote flux of lipid to skeletal muscle and regulate metabolic flexibility. We have now investigated the role of mitochondrial biogenesis in mediating these effects.</p> <p>Methods</p> <p>We tested the effect of leucine, calcitriol and calcium in regulation of mitochondrial mass using a fluorescence method and tested mitochondrial biogenesis regulatory genes as well mitochondrial component genes using real-time PCR. We also evaluated the effect of leucine on oxygen consumption with a modified perfusion system.</p> <p>Results</p> <p>Leucine (0.5 mM) increased mitochondrial mass by 30% and 53% in C2C12 myocytes and 3T3-L1 adipocytes, respectively, while calcitriol (10 nM) decreased mitochondrial abundance by 37% and 27% (p < 0.02). Leucine also stimulated mitochondrial biogenesis genes SIRT-1, PGC-1α and NRF-1 as well as mitochondrial component genes UCP3, COX, and NADH expression by 3–5 fold in C2C12 cells (p < 0.003). Adipocyte-conditioned medium reduced mitochondrial abundance (p < 0.001) and decreased UCP3 but increased PGC-1α expression in myocytes, suggesting a feedback stimulation of mitochondrial biogenesis. Similar data were observed in C2C12 myocytes co-cultured with adipocytes, with co-culture markedly suppressing mitochondrial abundance (p < 0.02). Leucine stimulated oxygen consumption in both C2C12 cells and adipocytes compared with either control or valine-treated cells. Transfection of C2C12 myocytes with SIRT-1 siRNA resulted in parallel suppression of SIRT-1 expression and leucine-induced stimulation of PGC-1α and NRF-1, indicating that SIRT-1 mediates leucine induced mitochondrial biogenesis in muscle cells.</p> <p>Conclusion</p> <p>These data suggest that leucine and calcitriol modulation of muscle and adipocyte energy metabolism is mediated, in part, by mitochondrial biogenesis.</p

Fairness-Aware Ranking in Search & Recommendation Systems with Application to LinkedIn Talent Search

We present a framework for quantifying and mitigating algorithmic bias in mechanisms designed for ranking individuals, typically used as part of web-scale search and recommendation systems. We first propose complementary measures to quantify bias with respect to protected attributes such as gender and age. We then present algorithms for computing fairness-aware re-ranking of results. For a given search or recommendation task, our algorithms seek to achieve a desired distribution of top ranked results with respect to one or more protected attributes. We show that such a framework can be tailored to achieve fairness criteria such as equality of opportunity and demographic parity depending on the choice of the desired distribution. We evaluate the proposed algorithms via extensive simulations over different parameter choices, and study the effect of fairness-aware ranking on both bias and utility measures. We finally present the online A/B testing results from applying our framework towards representative ranking in LinkedIn Talent Search, and discuss the lessons learned in practice. Our approach resulted in tremendous improvement in the fairness metrics (nearly three fold increase in the number of search queries with representative results) without affecting the business metrics, which paved the way for deployment to 100% of LinkedIn Recruiter users worldwide. Ours is the first large-scale deployed framework for ensuring fairness in the hiring domain, with the potential positive impact for more than 630M LinkedIn members.Comment: This paper has been accepted for publication at ACM KDD 201

Fairness Beyond Disparate Treatment & Disparate Impact: Learning Classification without Disparate Mistreatment

Automated data-driven decision making systems are increasingly being used to assist, or even replace humans in many settings. These systems function by learning from historical decisions, often taken by humans. In order to maximize the utility of these systems (or, classifiers), their training involves minimizing the errors (or, misclassifications) over the given historical data. However, it is quite possible that the optimally trained classifier makes decisions for people belonging to different social groups with different misclassification rates (e.g., misclassification rates for females are higher than for males), thereby placing these groups at an unfair disadvantage. To account for and avoid such unfairness, in this paper, we introduce a new notion of unfairness, disparate mistreatment, which is defined in terms of misclassification rates. We then propose intuitive measures of disparate mistreatment for decision boundary-based classifiers, which can be easily incorporated into their formulation as convex-concave constraints. Experiments on synthetic as well as real world datasets show that our methodology is effective at avoiding disparate mistreatment, often at a small cost in terms of accuracy.Comment: To appear in Proceedings of the 26th International World Wide Web Conference (WWW), 2017. Code available at: https://github.com/mbilalzafar/fair-classificatio

Dairy attentuates oxidative and inflammatory stress in metabolic syndrome123

Background: Oxidative and inflammatory stress are elevated in obesity and are further augmented in metabolic syndrome. We showed previously that dairy components suppress the adipocyte- and macrophage-mediated generation of reactive oxygen species and inflammatory cytokines and systemic oxidative and inflammatory biomarkers in obesity

Dietary fat and not calcium supplementation or dairy product consumption is associated with changes in anthropometrics during a randomized, placebo-controlled energy-restriction trial

Insufficient calcium intake has been proposed to cause unbalanced energy partitioning leading to obesity. However, weight loss interventions including dietary calcium or dairy product consumption have not reported changes in lipid metabolism measured by the plasma lipidome

Interaction Between Leucine and Phosphodiesterase 5 Inhibition in Modulating Insulin Sensitivity and Lipid Metabolism

Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects. Methods: We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO) mice. Results: Leucine (0.5 mM) exhibited significant synergy with subtherapeutic doses (0.1–10 nM) of PDE5-inhibitors (sildenafil and icariin) on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet). However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet) for 6 weeks reduced fasting glucose (38%, P,0.002), insulin (37%, P,0.05), area under the glucose tolerance curve (20%, P,0.01), and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for leucine–PDE5 inhibitor combinations