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

补充 Trans-10、Cis-12 CLA 改变脂肪细胞脂质代谢

• 批准号: 8604377
• 负责人: Laura Jane den Hartigh
• 金额: $ 12.98万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8604377
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Affect; Biochemical Pathway; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Central obesity; Chemotactic Factors; Conjugated Linoleic Acids; Diabetes Mellitus; Diet; Dyslipidemias; Eating; Energy Metabolism; Esterification; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Gene Expression; Glucose; Health; Heart Diseases; Hepatocyte; Human; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Investigation; Knowledge; Laboratory Study; Link; Lipids; Lipolysis; Liver; Locomotion; Measures; Mesentery; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Morphology; Mus; Myocardium; Obese Mice; Obesity; Obesity associated disease; Oxidative Stress; Pathway interactions; Phenotype; Population; Process; Production; Property; Protein Isoforms; Proteins; Reporting; Retroperitoneal Space; Risk; Skeletal Muscle; Superoxides; Supplementation; Surveys; Testing; Trans Fatty Acids; Triglycerides; Visceral; cardiovascular disorder risk; cytokine; dietary supplements; fatty acid oxidation; glucose tolerance; glucose uptake; in vivo; insulin sensitivity; insulin tolerance; lipid metabolism; macrophage; male; monocyte; mouse model; novel; public health relevance; research study; response; treatment strategy; uptake

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.

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减肥。 CLA 的一种特定亚型，即反式 10、顺式 12 (t10,c12) CLA，与减少肥胖有关，这是有益的，但同时会促进全身炎症、胰岛素抵抗和血脂异常，所有这些都可能是有害的。 t10,c12-CLA 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疾病，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潜在的长期不良健康影响的风险。因此，更好地了解 t10,c12-CLA 影响脂肪组织代谢的机制非常重要。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，培养的脂肪细胞中线粒体代谢显着增加，同时炎症和单核细胞趋化因子基因表达增加。具体而言，白色脂肪细胞中的 t10,c12-CLA 可增强线粒体脂肪酸氧化，而这一过程通常为棕色脂肪细胞、骨骼肌、心肌和肝细胞保留。我们的总体假设是，t10,c12-CLA 通过将白色脂肪细胞的脂质代谢改变为独特的棕色脂肪细胞样表型，从而导致脂肪组织中的脂质储存受损，但代价是引起脂肪组织的炎症变化。在此应用中，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，因为它与经常与肥胖相关的代谢状态有关。我们将进行体外实验来调查与增强脂肪酸氧化相关的其他机制，例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，以及暴露于t10,c12-CLA的脂肪细胞中的脂肪分解。为了评估 t10,c12-CLA 诱导的体内脂肪组织代谢变化，我们将向患有肥胖症的雄性 Ldlr-/- 小鼠补充一份 t10,c12-CLA，这与人类的补充情况相似。将评估全身重量、成分、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、巨噬细胞积累和脂肪酸氧化能力。随着对相关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。