Adipogenesis and Insulin Resistance

脂肪生成和胰岛素抵抗

• 批准号: 8741341
• 负责人: Arthur Sherman
• 金额: $ 3.12万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8741341
• 关键词: Adipocytes; Bolus Infusion; Caliber; Cell Size; Cells; Characteristics; Collaborations; Contracts; Defect; Diabetes Mellitus; Disease; Fatty acid glycerol esters; Functional disorder; Goals; Growth; Human; Individual; Insulin; Insulin Resistance; Investigation; Laws; Lead; Left; Lipids; Liver; Metabolic; Modeling; Muscle; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Normal Statistical Distribution; Obesity; Organ; Overweight; Pancreas; Pathogenesis; Population Study; Process; Property; Recording of previous events; Recruitment Activity; Reporting; Risk Factors; Rodent; Role; Tail; Time; Universities; Work; adipocyte differentiation; design; follow-up; glucose uptake; insulin secretion; insulin sensitivity; lipid biosynthesis; response; trend

For nearly the past decade we have been studying the relationship between insulin resistance and adipocyte size in a number of settings. The key ideas we have distilled from these investigations include: 1. Adipose cells vary widely in size from about 20 microns in diameter to well over 100 microns, befitting their unique role as cells that can expand and contract to take up and release lipid as needed. 2. The distributions are not typical unimodal Gaussian distributions but typically have a Gaussian-like peak of large cells and an exponential-like tail of small cells. We have interpreted the Gaussian peak as representing mature adipocytes and the tail as newer cells in the process of growing as they take up lipid. Dynamical models by others in the lab (see reports by Vipul Periwal, LBM) have confirmed that a hypothesized growth process incorporating newly recruited cells emerging with diameter around 20 microns and growing according to a size-dependent growth law naturally generates such distributions. A distinct nadir between the left tail and the right peak is found if cells are assume to grow slowly until they reach a threshold diameter of, say, 30 - 60 microns and then grow rapidly. In some individuals, both human and rodent, an additional peak of cells with intermediate diameter can be observed, which may even move to the right with time, suggesting a bolus of cells recruited close together in time that grows and joins the peak of mature cells. 3. We have correlated the characteristics of the size distributions, chiefly the fraction of small cells and the typical size of the large cells, with insulin resistance or sensitivity in a variety of study populations. Our initial study, in collaboration with the McLaughlin lab at Stanford University, examined moderately obese subjects (BMI near 30 kg/m2) who were insulin sensitive (IS) or insulin resistant (IR) and found that the insulin resistant group had an increased proportion of small cells. This was interpreted as a signature of impaired adipocyte development, which could result in impaired lipid storage capacity and lead to spillover of lipid to other organs poorly equipped to handle the fat load. Such spillover, or "ectopic fat" has been proposed to cause insulin resistance in muscle and liver and impaired insulin secretion in the pancreas. The study noted a trend toward larger large cells among the IR subjects, but this did not reach statistical significance. One would expect larger large cells given a smaller proportion of large cells if BMI and total fat mass are the same between the groups, as they were by design. A follow-up study with a larger group of subjects and a broader range of BMI has confirmed the increased proportion of small cells as well as larger large cells (see Ref. # 1 of this report). The increased size was also reported by us in Ref. # 1 of the 2012 report. A considerable body of evidence from other studies supports the notion that large cells are intrinsically less efficient at storing lipid than small cells (again, see report of Periwal, LBM, for a theoretical view of this). In summary, in all these cases the distribution of adipose cell sizes is related to metabolic status, but the particular response is dependent on the metabolic status and history of the subject. The results above, taken together, along with work in other sections of LBM, lead to the overall conclusion that large cell size is a primary risk factor for insulin resistance, along with an excess of small cells. We hypothesize that in untreated IR subjects the surplus of small cells reflects impaired differentiation. Indeed, the two properties may be related, as a defect in potential to recruit and enlarge new adipocytes may be compensated by enlargement of existing adipocytes beyond their healthy operating range.

近十年来，我们一直在研究胰岛素抵抗和脂肪细胞大小之间的关系，在许多设置。 我们从这些调查中提炼出的关键思想包括： 1.脂肪细胞的大小从直径约20微米到远超过100微米变化很大，适合它们作为可以根据需要膨胀和收缩以吸收和释放脂质的细胞的独特作用。 2.该分布不是典型的单峰高斯分布，而是典型地具有大单元的类高斯峰和小单元的类指数尾。 我们已经将高斯峰解释为代表成熟的脂肪细胞，并且将尾部解释为随着它们摄取脂质而处于生长过程中的新细胞。 实验室中其他人的动力学模型（见Vipul Periwal，LBM的报告）已经证实，一个假设的生长过程，包括直径约为20微米的新招募细胞，并根据大小依赖性生长定律生长，自然会产生这种分布。 如果假设细胞缓慢生长直到它们达到例如30 - 60微米的阈值直径，然后快速生长，则发现左尾和右峰之间的明显最低点。 在一些个体中，无论是人类还是啮齿动物，都可以观察到具有中等直径的细胞的额外峰，其甚至可以随时间向右移动，这表明在时间上聚集在一起的细胞团生长并加入成熟细胞的峰。 3.我们已经将大小分布的特征，主要是小细胞的分数和大细胞的典型大小，与各种研究人群中的胰岛素抵抗或敏感性相关联。 我们与斯坦福大学McLaughlin实验室合作的初步研究，检查了胰岛素敏感（IS）或胰岛素抵抗（IR）的中度肥胖受试者（BMI接近30 kg/m2），发现胰岛素抵抗组的小细胞比例增加。 这被解释为脂肪细胞发育受损的标志，这可能导致脂质储存能力受损，并导致脂质溢出到其他器官，无法处理脂肪负荷。 这种溢出或“异位脂肪”被认为会导致肌肉和肝脏中的胰岛素抵抗以及胰腺中胰岛素分泌受损。 该研究注意到IR受试者中有更大的大细胞的趋势，但这并没有达到统计学意义。 如果两组的BMI和总脂肪量相同，那么如果大细胞的比例较小，那么大细胞会更大。 一项针对更大受试者组和更广泛BMI范围的随访研究证实了小细胞和较大大细胞的比例增加（见本报告参考文献1）。 我们还在2012年报告的参考文献1中报告了增加的尺寸。 来自其他研究的大量证据支持这样的观点，即大细胞在储存脂质方面本质上不如小细胞有效（再次，参见Periwal，LBM的报告，以获得对此的理论观点）。 总之，在所有这些情况下，脂肪细胞大小的分布与代谢状态有关，但具体的反应取决于受试者的代谢状态和病史。 以上结果，连同沿着在LBM的其他部分中的工作，导致总体结论，大细胞尺寸是胰岛素抵抗的主要危险因素，沿着过量的小细胞。 我们假设在未经治疗的IR受试者中，小细胞的过剩反映了分化受损。 事实上，这两种性质可能是相关的，因为招募和扩大新脂肪细胞的潜力的缺陷可以通过扩大现有脂肪细胞超过其健康的操作范围来补偿。