Alterations in Adipocyte Lipid Metabolism by Trans-10, Cis-12 CLA Supplementation

描述(申请人提供)：共轭亚油酸(CLA)是一种天然的饮食反式脂肪酸，据报道，通过未知的机制促进减肥。共轭亚油酸的一种特定亚型，反式-10，顺式-12(t10，c12)共轭亚油酸，与减少肥胖有关，这是有益的，但同时也会促进全身炎症、胰岛素抵抗和血脂紊乱，所有这些都可能是有害的。T10，c12-CLA的这些看似相反的作用还没有在代谢综合征的背景下进行检验，代谢综合征是一种常见的情况，内脏肥胖与脂肪组织炎症、血脂异常和胰岛素抵抗有关。商业上可以买到的含有t10，c12-cla的CLA补充剂被广泛用于促进减肥，因此对体重和炎症的相反影响可能会使消费者面临潜在的长期不利健康影响的风险。因此，更好地了解t10，c12-CLA影响脂肪组织代谢的机制是很重要的。我们的初步研究已经开始探讨t10，c12-CLA降低肥胖的机制。我们已经确定，在培养的脂肪细胞中，线粒体代谢显著增加，伴随而来的是炎症和单核细胞趋化因子基因表达的增加。具体地说，白色脂肪细胞中的线粒体脂肪酸氧化被t10，c12-CLA增强，这一过程通常为棕色脂肪细胞、骨骼肌、心肌和肝细胞所保留。我们的总体假设是，t10，c12-CLA通过改变白色脂肪细胞的脂代谢，使其向独特的棕色脂肪细胞样表型转变，从而导致脂肪组织中的炎性变化，从而损害了脂肪组织中的脂肪储存。在这项应用中，我们将进一步研究t10，c12-CLA对脂肪细胞脂代谢和炎症的影响，因为它与经常与肥胖相关的代谢状态有关。我们将进行体外实验，以研究与增强脂肪酸氧化有关的其他机制，如葡萄糖或脂肪酸摄取的改变，脂肪酸的再酯化，脂滴相关蛋白的表达和功能，以及暴露于t10，c12-CLA的脂肪细胞的脂解作用。为了评估t10，c12-CLA在体内引起的脂肪组织代谢的变化，我们将向已证实肥胖的雄性Ldlr-/-小鼠补充一种t10，c12-CLA，这反映了人类的补充。将评估整体体重、成分、能量消耗、运动能力、生热能力和胰岛素敏感性，并将检查脂肪组织库(附睾部、腹股沟、肠系膜、腹膜后和肩胛下棕色)的质量、形态、巨噬细胞聚集和脂肪酸氧化能力。随着对参与其中的生化途径的进一步研究 对于t10，c12-CLA的脂肪细胞和代谢反应，有可能利用这种新型膳食补充剂的抗肥胖潜力，同时消除其对炎症和胰岛素抵抗的潜在不利影响。

DESCRIPTION (provided by applicant): Conjugated linoleic acid (CLA) is a natural dietary trans fatty acid reported to promote weight loss by unknown mechanisms. One specific isoform of CLA, trans-10, cis-12 (t10,c12) CLA, is associated with reduced adiposity, which is beneficial, while simultaneously promoting systemic inflammation, insulin resistance, and dyslipidemia, all of which could be detrimental. These seemingly opposing effects of t10,c12-CLA have not yet been examined in the context of the metabolic syndrome, a common condition in which visceral obesity is associated with adipose tissue inflammation, dyslipidemia, and insulin resistance. Commercially available CLA supplements containing t10,c12-CLA are widely used to facilitate weight loss, so the opposing effects on body weight and inflammation could put consumers at risk of the potential for long-term adverse health effects. It is therefore important to better understand mechanisms by which t10,c12-CLA affects adipose tissue metabolism. Our preliminary studies have begun to investigate mechanisms by which t10,c12-CLA reduces adiposity. We have determined that mitochondrial metabolism is substantially increased in cultured adipocytes, with concomitant increases in inflammatory and monocyte chemotactic factor gene expression. Specifically, mitochondrial fatty acid oxidation is enhanced by t10,c12-CLA in white adipocytes, a process normally reserved for brown adipocytes, skeletal muscle, cardiac muscle, and hepatocytes. Our overall hypothesis is that t10,c12-CLA contributes to impaired lipid storage in adipose tissue by altering the lipid metabolism of white adipocytes towards a unique brown adipocyte-like phenotype at the expense of causing inflammatory changes in adipose tissue. In this application, we will further examine the effects of t10,c12-CLA on adipocyte lipid metabolism and inflammation as it relates to the metabolic state frequently associated with obesity. We will perform in vitro experiments to survey additional mechanisms related to enhanced fatty acid oxidation, such as altered glucose or fatty acid uptake, re-esterification of fatty acids, expression and function of lipid droplet-associated proteins, and lipolysis in adipocytes exposed to t10,c12-CLA. To assess t10,c12- CLA-induced changes in adipose tissue metabolism in vivo, we will supplement male Ldlr-/- mice with established obesity with one precent t10,c12-CLA, which mirrors human supplementation. Whole body weight, composition, energy expenditure, locomotion, thermogenic capacity, and insulin sensitivity will be assessed, and adipose tissue depots (epididymal, inguinal, mesenteric, retroperitoneal, and subscapular brown) will be examined for mass, morphology, macrophage accumulation, and fatty acid oxidative capacity. With further investigation into the biochemical pathways involved in adipocyte and metabolic responses to t10,c12-CLA, it might be possible to harness the anti-obesity potential of this novel dietary supplement, while eliminating its potentially adverse effects on inflammation and insulin resistance.