第二型糖尿病的發生目前已知是多個胰島素反應組織，如脂肪、肝臟和肌肉等組織出現胰島素抗性所導致。Thiazolidinediones (TZDs)是一類化學合成的過氧化體增生受器 (peroxisome proliferator-activated receptor γ, PPARγ) 高親和性配體，目前被用來做為治療第二型糖尿病的藥物，具有降低全身性胰島素阻抗性及降血糖之效用。TZDs 的治療效果可能是源自於其對一個或多個組織中PPARγ作用後之結果。然而， PPARγ對於調控不同組織的胰島素敏感性之角色尚未完全釐清。因此，我們利用實驗室已建構的PPARγ低表達量小鼠 (PpargC/- mice)，來探討在一般餵食、高脂肪餵食及TZD給予之下， PPARγ調控不同組織的胰島素敏感性的角色。在我們之前的研究發現，PPARγ低表達量小鼠在副睪旁脂肪組織有脂肪缺失的現象，且伴隨著高脂血症及全身性胰島素抗性。因此，我們假設PPARγ的缺失會造成副睪旁脂肪組織中基因表現受損，並對胰島素出現抗性，進而導致全身性的胰島素抗性。首先，我們發現PPARγ低表達量小鼠在一般餵食下，其副睪旁脂肪組織的胰島素敏感性顯著低於野生型小鼠，且伴隨著代謝相關分子基因的表現量下降。然而，在PPARγ低表達量小鼠的鼠蹊部脂肪組織中，其胰島素敏感性相較於野生型小鼠卻有顯著升高，但其代謝相關基因的表現量則較沒有受到PPARγ缺失影響。在給予高脂肪飼料餵食下， PPARγ低表達量小鼠中，副睪旁脂肪組織的胰島素敏感性相較於野生型小鼠有更明顯下降情形，而鼠蹊部脂肪組織胰島素敏感性則仍有明顯增高現象。PPARγ低表達量小鼠中，肝臟和肌肉組織胰島素敏感性也受到高脂肪飼料餵食影響而些微降低。此外，PPARγ低表達量小鼠的副睪旁及鼠蹊部脂肪組織中，一些和代謝相關的基因表現量也都受到高脂肪餵食影響。有趣的是，當我們給予TZD後，PPARγ低表達量小鼠的全身性胰島素阻抗現象完全消失，而副睪旁及鼠蹊部脂肪組織、肝臟和肌肉組織的胰島素敏感性和野生型小鼠比較則無明顯差異。另外，在PPARγ低表達量小鼠的副睪旁脂肪組織中，大部分代謝基因的表現量也受到TZD的影響，而與野生型小鼠無明顯差異。進一步我們更發現在內生性PPARγ 表達量正常的情況下，TZD主要提升鼠蹊部脂肪的胰島素敏感性，然而，在內生性PPARγ 缺失情況下，TZD則主要是提升副睪旁脂肪組織的胰島素敏感性。綜合以上結果可知，內生性PPARγ對於副睪旁脂肪組織的胰島素敏感性和代謝功能維持是重要的，而此會進一步影響其他胰島素反應組織及全身性的胰島素敏感性。

Type 2 diabetes is accompanied by insulin resistance in multiple insulin-responsive tissues. Thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, are synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligands and anti-diabetic drugs that are used to reduce insulin resistance and hyperglycemia in patients with type 2 diabetes. The therapeutic effects of TZDs may be the integrated actions on PPARγ of one or more insulin-responsive tissues. However, the impact of PPARγ in maintenance of insulin sensitivity in different tissues is not fully clarified. We used mice with extremely low PPARγ level (PpargC/- mice) to dissect the role of PPARγ in insulin sensitivity of individual tissues under the condition of regular chow (RC), high-fat diet (HFD) and HFD with TZD (HFTZD). Our previous study showed that PPARγ deficiency leads to a selective fat loss in perigonadal depot, hyperlipidemia and systemic insulin resistance. Thus we hypothesized that PPARγ deficiency impaired gene expression profile and local insulin sensitivity in perigonadal fat, further contributing to systemic insulin resistance. First, we found that insulin sensitivity was selectively impaired in perigonadal fat with a concurrent reduction of gene expression profile in RC-fed PpargC/- mice. The insulin sensitivity of inguinal fat was not impaired, and most factors in this depot were not affected in RC-fed PpargC/- mice. After HFD feeding, PpargC/- mice had exaggeratedly impaired insulin sensitivity in perigonadal fat and increased insulin sensitivity in inguinal fat of PpargC/- mice. HFD also modestly affected the insulin sensitivity in liver and skeletal muscle in PpargC/- mice. Gene expression profiles in both perigonadal and inguinal fat depots, not liver and skeletal muscle, were affected by PPARγ deficiency in the condition of excess lipid load. Interestingly, TZD treatment reversed the systemic insulin resistance, which is associated with the normalization of local insulin sensitivity in perigonadal fat, liver and skeletal muscle. Consistently, the gene expression profile indicated that most factors involved in glucose and lipid metabolism in perigonadal fat were reversed to the same extent of Pparg+/+ mice. Furthermore, we found TZD exhibits its insulin-sensitizing effect predominantly through its action in inguinal fat in normal endogenous PPARγ expression, but through its action in perigonadal fat in endogenous PPARγ deficiency. In conclusion, our study demonstrates that the role of PPARγ in adipose tissue is more important than non-adipose tissue (liver and skeletal muscle) in maintenance of insulin sensitivity and functionality. Thus, normal level of endogenous PPARγ is required for maintenance of insulin sensitivity and functionality in perigonadal fat, which would further influence the insulin sensitivity of other insulin-responsive tissues and whole body.

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