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: 9033831
• 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/9033831
• 关键词: Adipocytes; Adipose tissue; Adverse effects; Affect; Biochemical Pathway; Body Composition; Body Weight; Body Weight decreased; Caloric Restriction; Carnitine O-Palmitoyltransferase; 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; 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; diabetogenic; dietary supplements; fatty acid oxidation; glucose tolerance; glucose uptake; in vivo; insulin sensitivity; insulin tolerance; lipid metabolism; macrophage; male; mitochondrial metabolism; monocyte; mouse model; novel; 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）：结合的亚油酸（CLA）是一种天然的饮食反式脂肪酸，据报道，据报道通过未知机制促进体重减轻。 CLA，Trans-10，CIS-12（T10，C12）CLA的一种特异性亚型与脂肪降低有关，肥胖性是有益的，同时促进了全身性炎症，胰岛素抵抗和血脂异常，所有这些都可能有害。在代谢综合征的背景下，尚未对T10，C12-CLA的看似相反的作用进行检查，在代谢综合征中，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体重减轻，因此对体重和炎症的相反影响可能会使消费者有可能产生长期不良健康影响的风险。因此，重要的是要更好地理解T10，C12-CLA会影响脂肪组织代谢的机制。我们的初步研究已开始研究T10，C12-CLA降低肥胖的机制。我们已经确定，培养的脂肪细胞中线粒体代谢大大增加，炎症和单核细胞趋化因子基因表达的伴随增加。具体而言，T10，白色脂肪细胞中的C12-CLA增强了线粒体脂肪酸的氧化，这是通常保留用于棕色脂肪细胞，骨骼肌，心脏肌肉和肝细胞的过程。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对脂肪组织中的脂质储存受损，以一种独特的棕色脂肪细胞样表型，而牺牲脂肪组织中炎症性变化为代价。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，以调查与增强的脂肪酸氧化有关的其他机制，例如葡萄糖或脂肪酸的摄取改变，脂肪酸的再酯化，脂质滴相关蛋白的表达和功能，以及与T10，C12-CLA相关的脂肪分解。为了评估T10，C12- CLA诱导的体内脂肪组织代谢的变化，我们将用一种预先的T10，C12-CLA补充雄性LDLR - / - 小鼠，这反映了人类补充。将评估全身体重，组成，能量消耗，运动，热能能力和胰岛素敏感性，并将检查脂肪组织库（附睾，腹膜，肠系膜，腹膜后，腹膜后骨和缩写棕色）的脂肪组织仓库，以了解质量，形态学，形态学，乳糖量积累和脂肪酸性氧化能力。随着对涉及的生化途径的进一步研究 对T10，C12-CLA的脂肪细胞和代谢反应，有可能利用这种新型饮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。