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

我们已经确定了线粒体动力学（裂变和融合）在摄食、能量和葡萄糖代谢的中央调节中的作用。我们发现，线粒体分裂对于下丘脑AgRP神经元适当促进摄食和体重增加至关重要，而线粒体融合对于下丘脑POMC神经元支持饱腹感和全身葡萄糖代谢的相关调节至关重要。在我们的初步研究中，我们还发现，选择性地干扰成年脂肪细胞的线粒体动力学对全身代谢有强大的影响，其中线粒体融合蛋白mitofusin 2 （Mfn2）的敲低导致小鼠体重迅速增加和摄食增加，同时下丘脑AgRP转录物升高。这些观察结果表明，体重增加是由线粒体分裂的中枢和外周支持的，并且，下丘脑或脂肪细胞中的线粒体动力学相互影响这些组织中的线粒体功能，从而影响行为和全身能量和葡萄糖代谢。为了支持这一点，我们在体外系统中发现，脂肪酸水平升高确实促进了线粒体裂变，而脂肪酸水平对体重增加至关重要。我们观察到不同的脂肪酸种类对线粒体动力学有不同的影响，并且改变饮食脂肪组成会导致食物摄入量增加和体重增加。综上所述，我们的观察结果推动了这项拨款提案的中心假设，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。我们提出以下具体目标来验证我们的假设：具体目标1将评估线粒体动力学在食物摄入和能量消耗中的作用，通过评估成熟脂肪细胞和中央摄食回路神经元中线粒体裂变和融合的影响。此外，目的1将探讨脂肪细胞的传入信号对摄食回路神经元功能的影响。特异性目标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在饮食脂肪影响的食物摄入中的作用。

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.