Short-term effects of overfeeding on metabolic risk in humans

在澳大利亚和世界其他地区，肥胖症的流行率正在迅速增加。肥胖与胰岛素抵抗密切相关，并在2型糖尿病的发展中发挥作用。然而，短期营养过剩对人类的影响仍不清楚。在拟议的研究中，我们将研究高脂肪喂养对瘦受试者、超重受试者和遗传上更容易患糖尿病（由于强烈的家族史）的受试者短期体重增加的影响。其目的是区分那些储存更多脂肪以应对过度喂养的个体的生理和内分泌特征。我们将确定这些个体之间的差异，以及他们是否在骨骼肌中参与脂肪氧化和能量产生的上调机制中存在缺陷，这可能有助于他们适应能量过剩。我们将寻找2型糖尿病风险的变化，我们将有可能确定参与这种反应的因素中的缺陷。我们还将重新检查个体在热量限制和减肥后。我们还计划通过啮齿类动物体内基因转移技术来确认在人类研究中已鉴定的参与脂肪氧化的候选基因的作用。这项研究将确定超重和瘦的受试者在面临过度喂养的挑战时是否表现相似。我们预计，由于代谢不稳定性和上调脂肪酸氧化和线粒体功能相关机制的能力降低，具有T2DM遗传易感性的个体将变得更加IR。通过描述对过度喂养的生理和内分泌反应，我们将建立可量化的标志物，使我们能够区分那些有风险的人，并确定药物或生活方式干预的新目标。

The prevalence of obesity is rapidly increasing in Australia and other parts of the world. Obesity is closely associated with insulin resistance and plays a role in the development of type 2 diabetes. However, the effects of short-term periods of over nutrition in humans remain unclear. In the proposed study, we will investigate the effects of short-term weight gain by high fat feeding in lean subjects, in subjects who are overweight and in subjects who are genetically more likely to develop diabetes (due to strong family history). The aims are to distinguish physiological and endocrine characteristics of individuals who store more fat in response to overfeeding. We will identify differences between these individuals and whether they have defects in upregulating machinery involved in fat oxidation and energy production in skeletal muscle that may help them adapt during to energy excess. We will look for changes in type 2 diabetes risk and we will have the potential to identify defects in factors that are involved in this response. We will also re-examine indivudals again after calorie restriction and weight loss. We also plan to confirm the role of the candidate genes involved in fat oxidation that have been identifieid in human studies by in vivo gene transfer technology in rodents. This study will determine whether overweight and lean subjects behave similarly when faced with an overfeeding challenge. We expect that individuals with a genetic predisposition for T2DM will become more IR, due to metabolic inflexibility and a decreased ability to upregulate machinery involved in fatty acid oxidation and mitochondrial function. By characterising the physiological and endocrine responses to overfeeding, we will establish quantifiable markers allowing us to distinguish those at risk and identify new targets for pharmacological or lifestyle intervention.