Delineating the regulation and function of gamma-synuclein in adipocyte lipid metabolism

肥胖是目前全球最大的医学挑战之一，因此显然需要找到新的潜在疗法来对抗这种日益普遍的疾病。脂肪组织由脂肪细胞组成，脂肪细胞是专门用于将脂肪安全储存在占据大部分细胞的一个大脂滴中的细胞。脂滴越大，脂肪细胞就越大，脂肪组织的总质量就越大。在肥胖症中，似乎脂肪组织的安全脂质储存能力可能被超过，脂质然后进入其他组织，造成有害影响。许多流行疾病都与这些脂质的负面影响有关，包括糖尿病，心脏病和某些形式的痴呆症。我们最近发现，抑制一种叫做γ-突触核蛋白的蛋白质可能会阻止肥胖的发展。γ-突触核蛋白在脂肪细胞中表达特别高。在缺乏γ-突触核蛋白的脂肪细胞中，脂滴的分解增加。然而，这并不会导致进入其他组织的脂质出现问题，因为似乎来自脂肪细胞中脂滴的脂质可以优先作为燃料燃烧，以提供能量，而来自饮食的脂质则不是。这种脂质的燃烧特别发生在专门的棕色脂肪细胞中，这些细胞能够做到这一点，然后将产生的能量以热量的形式消散。激活这一过程被认为是通过有效燃烧多余的脂质和浪费能量来治疗肥胖的潜在方法。我们发现，抑制γ-突触核蛋白可能有助于棕色脂肪细胞更有效地做到这一点。因此，总的来说，γ-突触核蛋白抑制的作用可能是既分解脂肪储存，又燃烧棕色脂肪细胞中的脂质。在这项研究中，我们的目标是了解1）γ-突触核蛋白基因如何在脂肪细胞中打开和关闭，2）γ-突触核蛋白如何精确地控制脂滴的分解，3）失去γ-突触核蛋白如何使棕色脂肪细胞燃烧更多的脂质。所有这些都可能提示改变γ-突触核蛋白水平或改变其工作方式以减轻体重和/或治疗与肥胖相关的疾病的方法。

Obesity represents one of the biggest current medical challenges worldwide and so there is a clear need to find new potential therapies to combat this increasingly prevalent condition. Fat tissue is comprised of adipocytes which are cells specialised to allow the safe storage of fat in one large lipid droplet occupying most of the cell. The bigger the lipid droplet is the larger the fat cell becomes and the greater the overall mass of fat tissue. In obesity, it appears that the safe lipid storage capacity of fat tissue may be exceeded and lipids then instead go to other tissues causing harmful effects. Many prevalent diseases are linked to the negative effects of these lipids including diabetes, heart disease and some forms of dementia. We have recently found that inhibiting a protein called gamma-synuclein might prevent the development of obesity. The gamma-synuclein protein is particularly highly expressed in fat cells. In fat cells lacking gamma-synuclein the breakdown of the lipid droplet is increased. However, this does not cause a problematic rise in lipids going to other tissues because it seems that the lipid that comes from the lipid droplet in the fat cell can be preferentially burnt as a fuel to provide energy in a way that lipids from the diet are not. This burning of lipids particularly occurs in specialised brown fat cells which are capable of doing this and then dissipating the energy generated as heat. Activating this process is seen a potential way to treat obesity by effectively burning excess lipids and wasting energy. We have found that inhibiting gamma-synuclein may help brown fat cells to do this more efficiently. Therefore, overall the effect of gamma-synuclein inhibition may be both to break down fat stores and then to burn the lipid in the brown fat cells. In this study we aim to understand 1) how the gamma-synuclein gene is switched on and off in fat cells, 2) how precisely gamma-synuclein controls the breakdown of the lipid droplet and 3) how losing gamma-synuclein makes brown fat cells burn more lipids. All of these may suggest ways to change levels of gamma-synuclein or alter the way it works to reduce body weight and/or treat the diseases associated with obesity.