The Role of Visceral Fatty Acids in Relation to Insulin Resistance

内脏脂肪酸在胰岛素抵抗中的作用

• 批准号: 8448337
• 负责人: MICHELLE T. FOSTER
• 金额: $ 15.01万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-04 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448337
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Anatomy; Animal Model; Animals; Area; Beds; Blood; Cells; Central obesity; Chronic; Data; Development; Diabetes Mellitus; Diet; Donor person; Enzymes; Etiology; Excision; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Future; Gluconeogenesis; Glucose Intolerance; Goals; Growth; Hepatic; Individual; Insulin; Insulin Resistance; Intra-abdominal; Link; Liver; Location; Maintenance; Mediating; Mesentery; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Portal vein structure; Procedures; Proliferating; Regulation; Relative (related person); Reporting; Risk; Role; Staging; System; Techniques; Testing; Training; Transgenic Animals; Transgenic Organisms; Transplantation; Triglycerides; Visceral; abdominal fat; abstracting; adrenergic; base; clinically relevant; diabetes risk; fatty acid oxidation; glucose tolerance; improved; lipid biosynthesis; liver function; novel; prevent; public health relevance; relating to nervous system; research study; trafficking; uptake

DESCRIPTION (provided by applicant): Project Summary / Abstract Chronic exposure of the liver to elevated FAs, as occurs on a high-fat diet (HFD), promotes liver gluconeogenesis, reduces enzymes of FA oxidation and increases hepatic lipogenesis, leading to increased liver triglyceride content (i.e., fatty liver) and insulin resistance. This is especially the case as visceral obesity develops. While there is evidence that dysregulation of FA storage within adipose tissue provides a fundamental link among obesity, insulin resistance and type-2 diabetes (T2D), the contribution of fatty acid trafficking in visceral fat is often underemphasized. Based on our preliminary data, we have hypothesized that excess FA flux to the liver via the hepatic portal vein is a key factor, and that it can occur for different reasons. We believe that this situation can be ameliorated, at least temporarily, by increasing the capacity of visceral fat (i.e., mesenteric white adipose tissue or WAT) to sequester FA from the blood, thereby reducing flux to the liver. In support of this, we have evidence that increasing visceral adipose mass due to local adipocyte proliferation or transplantation of adipose tissue into the mesenteric region improves glucose tolerance; i.e., visceral adipose tissue mass per se is not a reliable predictor of insulin resistance. We propose to test the hypothesis that insulin resistance/glucose intolerance can be reversed by procedures that promote adipocyte expansion and FA retention in the visceral bed. Specific Aims are: 1.) To test the hypothesis that DIO (HFD- induced obesity) increases hepatic insulin resistance in part due to insufficient removal of FA from blood by proliferating adipocytes. This will be accomplished by investigating small adipocyte growth-induced improvements in glucose tolerance via characterizing specific adipocyte cell stage and anatomic location in terms of the capacity to store and retain FA. We will also demonstrate if adipocyte proliferation induction is prevented, then concurrent improvement of glucose tolerance is prevented as well. Lastly, we will induce insulin resistance via a selective increase of portal FA influx to the liver. 2.) To test the hypothesis that the development of FA dysregulation in mature adipocytes is due to reduced insulin-mediated FA retention. We predict that transplantation-induced glycemic improvements result from adipose depot-specific differences in insulin-mediated actions within mature adipocytes, and that these in turn are related to the relative neural (i.e., sympathetic) activity in specific fat depots. We will compare the individual contribution of adrenergic-induced lipolytic effects and insulin FA uptake/anti-lipolytic effects on glucose tolerance in animals receiving different transplants. Collectively, these experiments will provide important new information on the regulation of liver functioning by FA released from adipocytes and/or diet. Further, the studies proposed have direct clinical relevance in that they may provide novel mechanisms as to how adipocyte dysregulation increases the risk of diabetes.

项目摘要/摘要肝脏长期暴露于高脂肪饮食（HFD）中FAs升高，可促进肝脏糖异生，降低FA氧化酶，增加肝脏脂肪生成，导致肝脏甘油三酯含量增加（即脂肪肝）和胰岛素抵抗。内脏性肥胖的发展尤其如此。虽然有证据表明脂肪组织内脂肪酸储存的失调是肥胖、胰岛素抵抗和2型糖尿病（T2D）之间的基本联系，但脂肪酸在内脏脂肪运输中的作用往往被低估。根据我们的初步数据，我们假设通过肝门静脉进入肝脏的过量FA通量是一个关键因素，并且可能由于不同的原因而发生。我们相信这种情况可以改善，至少是暂时的，通过增加内脏脂肪（即肠系膜白色脂肪组织或WAT）从血液中隔离FA的能力，从而减少流向肝脏的流量。为了支持这一点，我们有证据表明，由于局部脂肪细胞增殖或脂肪组织移植到肠系膜区域，内脏脂肪量增加可改善葡萄糖耐量；也就是说，内脏脂肪组织质量本身并不是胰岛素抵抗的可靠预测指标。我们建议测试胰岛素抵抗/葡萄糖耐受不良可以通过促进脂肪细胞扩张和FA在内脏床的保留来逆转的假设。具体目标是：1)；为了验证DIO （HFD诱导的肥胖）增加肝脏胰岛素抵抗的假设，部分原因是脂肪细胞增殖导致血液中FA的去除不足。这将通过研究小脂肪细胞生长诱导的葡萄糖耐量的改善来完成，通过表征特定脂肪细胞阶段和解剖位置来存储和保留FA的能力。我们还将证明，如果脂肪细胞增殖诱导被阻止，那么糖耐量的同时改善也被阻止。最后，我们将通过选择性地增加门静脉FA流入肝脏来诱导胰岛素抵抗。2)。为了验证成熟脂肪细胞中FA失调的发展是由于胰岛素介导的FA保留减少的假设。我们预测，移植诱导的血糖改善是由于成熟脂肪细胞中胰岛素介导作用的脂肪库特异性差异造成的，而这些差异反过来又与特定脂肪库的相关神经（即交感神经）活动有关。我们将比较接受不同移植的动物肾上腺素能诱导的脂溶作用和胰岛素FA摄取/抗脂溶作用对糖耐量的个体贡献。总的来说，这些实验将为脂肪细胞和/或饮食中释放的FA对肝功能的调节提供重要的新信息。此外，提出的研究具有直接的临床相关性，因为它们可能为脂肪细胞失调如何增加糖尿病风险提供新的机制。

项目成果

Ovariectomy results in differential shifts in gut microbiota in low versus high aerobic capacity rats.

• DOI: 10.14814/phy2.12488
• 发表时间: 2015-08
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Cox-York KA;Sheflin AM;Foster MT;Gentile CL;Kahl A;Koch LG;Britton SL;Weir TL
• 通讯作者: Weir TL

So as we worry we weigh: Visible burrow system stress and visceral adiposity.

因此，当我们担心时，我们会权衡：可见的洞穴系统压力和内脏肥胖。

• DOI: 10.1016/j.physbeh.2017.01.019
• 发表时间: 2017
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Foster,MichelleT