Ratner Cecilia, Madsen Andreas Nygaard, Kristensen Line Vildbrad, Skov Louise Julie, Pedersen Katrine Seide, Mortensen Ole Hartvig, Knudsen Gitte Moos, Raun Kirsten, Holst Birgitte
Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark; Section for Metabolic Receptology and Enteroendocrinology, The Novo Nordisk Foundation Center for basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark;
Department of Biomedical Sciences, Cellular and Metabolic Research Section, Symbion, Copenhagen, Denmark;
Am J Physiol Regul Integr Comp Physiol. 2015 Jun 1;308(11):R973-82. doi: 10.1152/ajpregu.00219.2014. Epub 2015 Apr 8.
To characterize mechanisms responsible for fat accumulation we used a selectively bred obesity-prone (OP) and obesity-resistant (OR) rat model where the rats were fed a Western diet for 76 days. Body composition was assessed by magnetic resonance imaging scans, and as expected, the OP rats developed a higher degree of fat accumulation compared with OR rats. Indirect calorimetry showed that the OP rats had higher respiratory exchange ratio (RER) compared with OR rats, indicating an impaired ability to oxidize fat. The OP rats had lower expression of carnitine palmitoyltransferase 1b in intra-abdominal fat, and higher expression of stearoyl-CoA desaturase 1 in subcutaneous fat compared with OR rats, which could explain the higher fat accumulation and RER values. Basal metabolic parameters were also examined in juvenile OP and OR rats before and during the introduction of the Western diet. Juvenile OP rats likewise had higher RER values, indicating that this trait may be a primary and contributing factor to their obese phenotype. When the adult obese rats were exposed to the orexigenic and adipogenic hormone ghrelin, we observed increased RER values in both OP and OR rats, while OR rats were more sensitive to the orexigenic effects of ghrelin as well as ghrelin-induced attenuation of activity and energy expenditure. Thus increased fat accumulation characterizing obesity may be caused by impaired oxidative capacity due to decreased carnitine palmitoyltransferase 1b levels in the white adipose tissue, whereas ghrelin sensitivity did not seem to be a contributing factor.
为了确定导致脂肪堆积的机制，我们使用了一种选择性培育的易肥胖（OP）和抗肥胖（OR）大鼠模型，这些大鼠被喂食西方饮食76天。通过磁共振成像扫描评估身体组成，正如预期的那样，与OR大鼠相比，OP大鼠出现了更高程度的脂肪堆积。间接量热法显示，与OR大鼠相比，OP大鼠的呼吸交换率（RER）更高，表明其氧化脂肪的能力受损。与OR大鼠相比，OP大鼠腹部脂肪中肉碱棕榈酰转移酶1b的表达较低，皮下脂肪中硬脂酰辅酶A去饱和酶1的表达较高，这可以解释更高的脂肪堆积和RER值。在引入西方饮食之前和期间，还对幼年OP和OR大鼠的基础代谢参数进行了检查。幼年OP大鼠同样具有较高的RER值，表明该特征可能是其肥胖表型的主要促成因素。当成年肥胖大鼠暴露于促食欲和促脂肪生成激素胃饥饿素时，我们观察到OP和OR大鼠的RER值均增加，而OR大鼠对胃饥饿素的促食欲作用以及胃饥饿素诱导的活动和能量消耗减弱更为敏感。因此，肥胖所特有的脂肪堆积增加可能是由于白色脂肪组织中肉碱棕榈酰转移酶1b水平降低导致氧化能力受损所致，而胃饥饿素敏感性似乎不是一个促成因素。
