Elucidation of the molecular mechanisms underlying insulin and exercise-induced effects on metabolism and vascular cells

抵抗素最初被鉴定为脂肪细胞分泌的蛋白质，其抑制胰岛素作用和脂肪分化。鉴定了与抗肿瘤蛋白同源的三种蛋白质，并将其命名为抵抗素样分子（RELM）α、β和γ。抵抗素和RELMα在脂肪中大量表达，但RELMβ和RELMγ主要从肠道分泌。由于营养成分对胰岛素敏感性有很大影响，因此我们研究了食物中各种营养因子对胰岛素家族蛋白表达的调节作用。首先，给小鼠喂以不同营养成分（高碳水化合物、高蛋白和高脂肪）的食物两周。高蛋白和高碳水化合物饮食显著抑制肠道中RELMβ mRNA的表达，而高脂肪饮食轻微但不显著地上调肠道中RELMβ mRNA的表达。在附睾脂肪中，高碳水化合物饮食使RELMβ表达显著降低，而RELMβ表达无变化。考虑到人类既没有RELMα也没有RELMγ，我们随后的研究集中在RELMβ表达上。我们使用人结肠癌细胞系LS 174 T。胰岛素和TNFα以及硬脂酸（一种饱和游离脂肪酸）处理可上调RELMβ表达，而D-葡萄糖可下调RELM β表达。这些结果表明，RELMβ的表达直接受营养素如葡萄糖和饱和游离脂肪酸（包括硬脂酸）以及激素（包括胰岛素和TNFα）的调节。这些调节可能在营养相关的胰岛素抵抗诱导中发挥重要作用。

Resistin was initially identified as a protein, secreted by adipocytes, which inhibits insulin action and adipose differentiation. The three proteins homologous to resistin were identified and given the names resistin-like molecules (RELM) α, β and γ. Resistin and RELMα are abundantly expressed in adipose, but RELMβ and RELMγ are secreted mainly from the gut. Since nutrient composition greatly affects insulin sensitivity, we investigated the regulatory effects of various nutritional factors in food on the expressions of resistin family proteins.First, mice were given diets with different nutritional compositions (high-carbohydrate, high-protein and high-fat) for two weeks. RELMβ mRNA expression in the intestines was markedly suppressed by the high-protein and high-carbohydrate diets, while slightly but not significantly upregulated by the high-fat diet. In the epididymal fat, resistin expression was unchanged, while RELMβ expression was markedly decreased by the high-carbohydrate diet. Taking into consideration that humans have neither RELMα nor RELMγ, our subsequent studies focused on RELMβ expression. We used the human colon cancer cell line LS174T. Treatments with insulin and TNFα as well as stearic acid, a saturated free fatty acid, upregulated RELMβ expression, while D-glucose downregulated RELMβ. These results suggest RELMβ expression to be regulated directly by nutrients such as glucose and saturated free fatty acids including stearic acid, as well as by hormones including insulin and TNFα. These regulations may play an important role in the nutrient-associated induction of insulin resistance.