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(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.

(1) 背景：关于高脂肪饮食（HFD）对肝脂质沉积和胰岛素抵抗的脂肪库代谢的长期动态变化的研究较少。本研究调查了 HFD 产生的动态变化以及功能失调的脂肪库对胰岛素抵抗和肝脂质代谢的影响。

(2) 方法：用标准饲料或 HFD（45%卡路里脂肪）喂养的小鼠，在 6、10、20 和 30 周时采集三个脂肪库（肝脏和血液）。测量肥胖发生、生热作用、细胞外基质重塑、炎症和组织胰岛素抵抗的基因标志物的变化。

(3) 结果：HFD 的早期反应是体重增加、肝脏中少量脂质沉积、脂肪细胞增大和脂肪生成。后期变化是功能性脂肪库功能障碍、肝脏脂肪增加、胰岛素抵抗（通过 ITT 变化显示），同时炎症标志物增加、纤维化增加（纤维化增加 2 倍以上，从第 6 周开始，<0.05），以及白色脂肪库中出现冠细胞。后来，变化并没有增加热量摄入引起的产热标志物，WAT 中的 UCP1 和 PRDM16 蛋白减少。

(4) 结论：HFD 喂养最初增加了脂肪细胞的直径和数量，但后来的变化导致脂肪库功能失调，限制了脂肪组织的扩张，改变了脂肪库中的棕色/米色比例，导致异位脂质沉积和胰岛素抵抗。