At similar weight loss, dietary composition determines the degree of glycemic improvement in diet-induced obese C57BL/6 mice

Background
Achieving weight loss is the cornerstone of the treatment of the metabolic consequences of obesity, in particular of glucose intolerance.
Objective
To determine whether improvement in glucose control depends on dietary macronutrient composition of the diet at identical weight loss.
Materials and methods
Twenty-two weeks old diet-induced obese C57BL/6 mice lost weight through caloric restriction on normal chow (R-NC) or high fat diet (R-HF). Control mice were fed normal chow (LEAN) or high fat diet (OBESE) ad libitum. Body weight and composition were assessed after 8 weeks of dietary intervention. Glucose homeostasis was evaluated by intraperitoneal glucose tolerance tests (IPGTT). Epididymal white adipose (eWAT) and hepatic tissues were analyzed by immunohistochemistry and RT-qPCR.
Results
By 30 weeks of age, the body weight of the mice on R-NC (31.6±1.7g, mean±SEM) and R-HF (32.3±0.9g) was similar to LEAN mice (31.9±1.4g), while OBESE mice weighed 51.7±2.4g. Glucose tolerance in R-NC was better than in LEAN mice (69% AUC IPGTT, P 0.0168) whereas R-HF mice remained significantly less glucose tolerant (125% AUC IPGTT, P 0.0279 vs LEAN), despite identical weight loss. The eWAT pads and adipocyte size were similar in LEAN and R-NC mice, while the eWAT pad size of R-HF was 180% of R-NC (P < 0.0001) and the average adipocyte size of R-HF mice was 134% of R-NC fed mice (P 0.0285). No LEAN or R-NC mice had hepatic steatosis, in contrast to 28.6% of R-HF mice. Compared to OBESE mice, inflammatory markers were lower in eWAT and liver tissue of R-NC, but not in R-HF mice. Measures of visceral adiposity correlated well with glucose tolerance parameters.
Conclusions
In mice, caloric restriction on a normal chow diet improved glucose tolerance significantly more when identical weight loss was achieved on a high fat diet.

背景：体重减轻是肥胖代谢并发症（尤其是葡萄糖耐受不良）治疗的核心基石。
研究目的：本研究旨在明确，在体重减轻幅度一致的前提下，血糖控制的改善是否取决于膳食宏量营养素的组成。
材料与方法：选取22周龄的饮食诱导肥胖C57BL/6小鼠，通过普通饲料热量限制组（R-NC）或高脂饲料热量限制组（R-HF）实现体重减轻；对照组小鼠分别自由摄食普通饲料（LEAN）或高脂饲料（OBESE）。膳食干预8周后，检测小鼠体质量及体成分。通过腹腔葡萄糖耐量试验（intraperitoneal glucose tolerance test, IPGTT）评估葡萄糖稳态，采用免疫组织化学法及实时定量聚合酶链反应（real-time quantitative polymerase chain reaction, RT-qPCR）对附睾白色脂肪组织（epididymal white adipose tissue, eWAT）与肝组织进行分析。
结果：至30周龄时，普通饲料热量限制组（R-NC）小鼠体质量为(31.6±1.7)g（均值±标准误，SEM），高脂饲料热量限制组（R-HF）为(32.3±0.9)g，与对照组普通饲料组（LEAN）的(31.9±1.4)g无显著差异；而高脂饲料自由摄食组（OBESE）小鼠体质量达(51.7±2.4)g。尽管各组体重减轻幅度一致，普通饲料热量限制组（R-NC）小鼠的葡萄糖耐量优于对照组普通饲料组（LEAN）（腹腔葡萄糖耐量试验曲线下面积为LEAN组的69%，P=0.0168），而高脂饲料热量限制组（R-HF）小鼠的葡萄糖耐量仍显著低于LEAN组（曲线下面积为LEAN组的125%，P=0.0279）。LEAN组与R-NC组小鼠的附睾白色脂肪组织垫重及脂肪细胞大小均无显著差异；而R-HF组小鼠的附睾白色脂肪组织垫重为R-NC组的180%（P<0.0001），平均脂肪细胞大小为R-NC组的134%（P=0.0285）。LEAN组与R-NC组小鼠均未出现肝脂肪变性，而R-HF组小鼠的肝脂肪变发生率为28.6%。与OBESE组相比，R-NC组小鼠附睾白色脂肪组织与肝组织中的炎症标志物水平更低，但R-HF组无此差异。内脏脂肪含量指标与葡萄糖耐量参数呈显著相关。
结论：在小鼠模型中，若实现相同幅度的体重减轻，普通饲料热量限制相比高脂饲料热量限制，可更显著地改善葡萄糖耐量。