The role of mitochondrial dynamics in diet-influenced regulation of food intake and adiposity

线粒体动力学在饮食影响的食物摄入和肥胖调节中的作用

• 批准号: 10154482
• 负责人: TAMAS L HORVATH
• 金额: $ 58.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154482
• 关键词: Ablation; Adipocytes; Adipose tissue; Adult; Affect; Animals; Applications Grants; Behavior; Body Weight; Brain; Cell model; Chimeric Proteins; Data; Development; Diet; Dietary Fats; Down-Regulation; Dynamin; Eating; Energy Intake; Energy Metabolism; Fatty Acids; Fatty acid glycerol esters; Feeding behaviors; Female; Food Energy; Food Intake Regulation; Hela Cells; High Fat Diet; Hypothalamic structure; In Vitro; Knock-out; Lead; Leptin; Mediating; Metabolism; Mitochondria; Molecular; Morphology; Mus; Neurons; Obesity; Palmitates; Peptides; Peripheral; Phenotype; Process; Proteins; Regulation; Role; Satiation; Signal Transduction; System; Testing; Tissues; Transcript; Weight Gain; Work; cell type; diet-induced obesity; dietary; fatty acid oxidation; feeding; glucose metabolism; in vivo; knock-down; lean body mass; male; neuronal circuitry; rapid weight gain; response

We have identified a role for mitochondrial dynamics (fission and fusion) in central regulation of feeding, energy- and glucose metabolism. We showed that mitochondrial fission is important for proper promotion of feeding and body weight gain by hypothalamic AgRP neurons, while mitochondrial fusion is critical for hypothalamic POMC neurons to support satiety and related adjustment of systemic glucose metabolism. In our preliminary studies we also found that interference with mitochondrial dynamics selectively in adult adipocytes has a robust impact on systemic metabolism, in which knockdown of the mitochondrial fusion protein, mitofusin 2 (Mfn2), resulted in rapid weight gain and elevated feeding of mice with concomitant elevations in hypothalamic transcripts for AgRP. These observations indicate weight gain is supported both centrally and peripherally by mitochondrial fission, and, that mitochondrial dynamics in either of the hypothalamus or adipocytes reciprocally impacts mitochondrial function in these tissues to affect behavior and systemic energy and glucose metabolism. In support of this, we revealed in an in vitro system that elevated fatty acid levels, which are critical for weight gain do promote mitochondrial fission. We observed that different fatty acids species have different effects on mitochondrial dynamics, and that altering dietary fat composition alone results in elevated in food intake and body weight gain. Taken together our observations gave impetus to the central hypothesis of this grant proposal that mitochondrial fission is a key dietary-influenced mechanism both in the hypothalamus and adipocytes that regulates body weight and adiposity. We propose the following Specific Aims to test our hypothesis: Specific aim 1 will assess the role of mitochondrial dynamics in food intake and energy expenditure by assessing the effects of both altered mitochondrial fission and fusion in mature adipocytes and in central feeding circuitry neurons. In addition, aim 1 will explore the afferent signaling from adipocytes that impacts the function of feeding circuitry neurons. Specific Aim 2 will use both in vitro and in vivo approaches to establish the role of hypothalamic and adipocyte mitochondrial dynamics on dietary fat-influenced food intake.

我们已经确定了线粒体动力学（裂变和融合）在进食，能量和葡萄糖代谢的中心调节中的作用。我们表明，线粒体裂变对于通过下丘脑AGRP神经元正确促进喂养和体重增加至关重要，而线粒体融合对于下丘脑POMC神经元至关重要，以支持饱腹感和相关调整系统性葡萄糖代谢。在我们的初步研究中，我们还发现，在成年脂肪细胞中选择性地干扰线粒体动力学对系统性代谢有强大的影响，在这种动力学中，线粒体融合蛋白2（MFN2）的敲低敲低是体重增加和升高型均具有浓度升高的小鼠，并导致升高的高度升高。这些观察结果表明，通过线粒体裂变在中心和外围支持体重增加，并且在下丘脑或脂肪细胞中的任何一个中的线粒体动力学都相互影响会影响这些组织中的线粒体功能，以影响行为能量和全身性能量和全身性化的代谢。为了支持这一点，我们在体外系统中揭示了升高脂肪酸水平，这对于体重增加至关重要，确实会促进线粒体裂变。我们观察到，不同的脂肪酸物种对线粒体动力学有不同的影响，并且仅改变饮食脂肪组成会导致食物摄入和体重增加的升高。综上所述，我们的观察结果推动了这一赠款提议的中心假设，即线粒体裂变是下丘脑和脂肪细胞中调节体重和肥胖的关键饮食影响机制。我们提出了以下特定目的来检验我们的假设：特定目标1将通过评估成熟脂肪细胞和中央饲料电路神经元中线粒体裂变和融合的影响，评估线粒体动力学在食物摄入和能量消耗中的作用。此外，AIM 1将探索影响喂养电路神经元功能的脂肪细胞的传入信号传导。特定的目标2将使用体外和体内方法来确定下丘脑和脂肪细胞线粒体动力学对饮食脂肪影响的食物摄入的作用。