脂肪缺失是指體內儲存脂質的脂肪組織產生缺失的現象，並且和胰島素阻抗、糖尿病及血脂異常有很大關聯性。PPARγ 在轉錄因子的分類上，它是屬於nuclear receptor 的子家族成員，配體(ligand) 對PPARγ的結合，使得轉錄輔抑制子從而脫離，並促使轉錄輔活化子返回與PPARγ結合，結合到標的基因促進轉錄作用。Thiazolidinedione (TZD) 即是一類化學合成的PPARγ 高親合性配體，目前臨床上應用於治療糖尿病。PPARγ最主要表現在脂肪組織，並且PPARγ 在調控脂肪細胞分化過程佔有樞紐的重要角色。此外，PPARγ 的活化會促進有關脂肪酸攝取的基因表現，並且在脂質代謝佔有重要角色。在我們之前建構的PPARγ低表達量小鼠具有體重減少及總脂肪組織減少現象。有趣的是，我們發現脂肪組織減少的區域，主要是副睪旁脂肪組織，而鼠蹊部脂肪組織則無異常減少現象。因此，我們認為在PPARγ低表達量小鼠的副睪旁脂肪組織中的脂肪細胞具有不同的分化調控機制參與其中。實驗結果發現，野生型及PPARγ低表達量小鼠，熱量的攝取、糞便中三酸甘油脂含量及體溫產熱並沒有差異。PPARγ低表達量小鼠在副睪旁脂肪缺失下，也伴隨著血中高三酸甘油脂及高游離脂肪酸，過多異位性脂質累積在肌肉中及胰島素阻抗情形。此外，我們發現具有PPRE 且與調控脂肪酸、甘油攝取及三酸甘油脂合成有關的基因，aP2, AQP7, Glu4 和PEPCK，在PPARγ低表達量小鼠的副睪旁脂肪組織，其表現量都有顯著降低，但在鼠蹊部脂肪組織則無明顯差異。我們針對在脂肪分化過程中不同時期的轉錄因子做偵測。PPARγ低表達量小鼠的PPARγ 訊息核醣核酸及蛋白質表現量在副睪旁脂肪組織及鼠蹊部脂肪組織都大幅降低。有趣的是，我們發現C/EBPα表現量，只有單獨降低在PPARγ低表達量小鼠的副睪旁脂肪組織，但在鼠蹊部脂肪組織則無顯著差異。在體外實驗方面，PPARγ低表達量小鼠的副睪旁脂肪細胞，其累積的脂質含量大量降低，而鼠蹊部脂肪細胞累積的脂質含量，則無顯著差異。我們也想探討在PPARγ低表達下，高脂環境下及PPARγ活化狀態下，對代謝調控的反應，於是我們施予老鼠高脂飲食(HF)及含有PPARγ配體成分的高脂飲食 (HF-TZD)。在給予HF及HF-TZD後，PPARγ低表達量小鼠的體重增長幅度依然較野生型小鼠低，並且副睪旁脂肪缺失的情形依然存在。然而在HF-TZD飲食下，過多異位性三酸甘油脂累積於肌肉的情況卻有改善回來。有趣的是，在HF-TZD 飲食下，胰島素阻抗情況也回復至正常。綜合以上所述，當PPARγ低表達下，C/EBPα表現下降似乎是決定PPARγ低表達量小鼠的副睪旁脂肪細胞分化能力降低的主因。此外，在當PPARγ低表達下，及使給予TZD 活化PPARγ，副睪旁脂肪缺失情形依然存在。由此，由我們結果證明，PPARγ對於不同區域的脂肪組織中的脂肪細胞分化，具有不同調控機制。

Lipodystrophy, characterized by loss of fat stores in some anatomic sites,is frequently associated with marked insulin resistance, diabetes mellitus and dyslipidemia. PPARγ is a ligand-dependent transcription factor which releases bound corepressors and recruits coactivator for transcriptional activation upon ligand binding. Thiazolidinediones (TZDs), are high-affinity synthetic agonists, have been widely used as insulin-sensitizing agents to treat type 2 diabetes. PPARγ is expressed mainly in adipose tissue, where it orchestrates the transcriptional cascade to regulate adipocyte differentiation. PPARγ also plays a key role in lipid metabolism, and its activation leads to upregulation of genes that mediate free fatty acid (FFA) uptake. We have previously generated PPARγ hypomorphic mice (PPARγC/-) which exhibit reduced body weight and total fat mass. Interestingly, the loss of fat mass is selectively in gonadal depot without significant change in inguinal depot throught lifespan. Thus we hypothesized that differential regulation of adipocyte differentiation is involved in the loss of gonadal depot in PPARγC/- mice. First, we found that the energy homeostasis was not different between PPARγ+/+ and PPARγC/- mice, evidenced by normal energy intake, fecal triglyceride output and thermogenesis. The reduction of gonadal fat depot in PPARγC/- mice was associated with increase of serum triglyceride and FFA, ectopic triglyceride deposition in muscle, and decrease of insulin sensitivity. Moreover, genes containing PPRE, such as aP2, AQP7, Glu4 and PEPCK, which regulate lipid uptake and synthesis, were downregulated in gonadal depot but not in inguinal depot of PPARγC/- mice. Adipocyte differentiation involves a temporally regulated set of gene-expression events. The levels of PPARγ mRNA and protein were comparably decreased in both gonadal and inguinal depot of PPARγC/- mice. Interestingly, thr level of C/EBPα was only decreased in gonadal depot without significant change in inguinal depot of PPARγC/- mice. The in vitro adipogenesis demonstrated that lipid accumulation was impaired in gonadal adipocyte, but not inguinal adipocyte of PPARγC/- mice. To examine the effects of PPARγ hypomorph on metabolic regulation of high-fat feeding and PPARγ activation, we fed mice with HF and HF-TZD. After feeding HF and HF-TZD treatment, PPARγ C/- mice gained less weight and their gonadal depot remained lipodystrophic. The phenomenon of ectopic muscle triglyceride accumulation was reversed upon HF-TZD treatment. Interestingly, the insulin resistence was abolished after HF-TZD feed. Together, C/EBPα is likely the regulator under limited availability of PPARγ leading to inhibition of adipogenesis in gonadal fat of PPARγ hypomorphic mice. In addition, residual PPARγ is not sufficient to rescue gonadal depot lipodystrophy in response TZD, but is sufficient to reverse the ectopic muscle triglyceride accumulation and insulin resistence in PPARγC/- mice. Thus our results demonstrate that PPARγ play an important role in differential regulation of adipocyte differentiation in various depots.

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