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

描述（由申请人提供）：共轭亚油酸（CLA）是一种天然膳食反式脂肪酸，据报道可通过未知机制促进体重减轻。CLA的一种特异性同种型，反式-10，顺式-12（t10，c12）CLA，与减少肥胖相关，这是有益的，同时促进全身性炎症、胰岛素抵抗和血脂异常，所有这些都可能是有害的。t10，c12-CLA的这些看似相反的作用尚未在代谢综合征的背景下进行研究，代谢综合征是一种常见的疾病，其中内脏肥胖与脂肪组织炎症，血脂异常和胰岛素抵抗有关。含有t10，c12-CLA的市售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使消费者面临长期不良健康影响的风险。因此，重要的是要更好地了解t10，c12-CLA影响脂肪组织代谢的机制。我们的初步研究已经开始调查t10，c12-CLA减少肥胖的机制。我们已经确定，线粒体代谢在培养的脂肪细胞中显著增加，伴随着炎症和单核细胞趋化因子基因表达的增加。具体而言，线粒体脂肪酸氧化被白色脂肪细胞中的t10，c12-CLA增强，该过程通常保留用于棕色脂肪细胞、骨骼肌、心肌和肝细胞。我们的总体假设是，t10，c12-CLA通过改变白色脂肪细胞的脂质代谢朝向独特的棕色脂肪细胞样表型，以引起脂肪组织中的炎性变化为代价，导致脂肪组织中的脂质储存受损。在本申请中，我们将进一步研究t10，c12-CLA对脂肪细胞脂质代谢和炎症的影响，因为它涉及到经常与肥胖相关的代谢状态。我们将进行体外实验，以调查其他机制相关的增强脂肪酸氧化，如改变葡萄糖或脂肪酸的摄取，脂肪酸的再酯化，脂滴相关蛋白的表达和功能，以及脂肪细胞暴露于t10，c12-CLA的脂解。为了评估t10，c12-CLA诱导的体内脂肪组织代谢变化，我们将向已确定肥胖的雄性Ldlr-/-小鼠补充一种t10，c12-CLA，这反映了人类补充。将评估全身重量、组成、能量消耗、运动、产热能力和胰岛素敏感性，并检查脂肪组织库（附睾、腹股沟、肠系膜、腹膜后和肩胛下棕色）的质量、形态、巨噬细胞蓄积和脂肪酸氧化能力。随着对参与的生化途径的进一步研究， 脂肪细胞和代谢对t10，c12-CLA的反应，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.