Hyperinsulinemia plays a causal role in adipose expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. We investigated the effects of genetically reducing insulin production on uncoupling and oxidative mitochondrial proteins in liver, skeletal muscle, white adipose tissue (WAT), and brown adipose tissue (BAT). Male Ins1^+/+ or Ins1^+/- littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. Replicating our previous observations, HFD increased fasting hyperinsulinemia, and Ins1^+/- mice had significantly lower circulating insulin compared with Ins1^+/+ littermates. Fasting glucose and body weight were not different between genotypes. We did not observe significant differences in liver in skeletal muscle. In mesenteric WAT, Ins1^+/- mice had reduced Ndufb8 and Sdhb. Ucp1 was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg abundance. In inguinal WAT, Ins1^+/- mice exhibited significant increases in oxidative complex proteins, independent of diet, without affecting Ucp1, Pparg, or Prdm16:Pparg association. In BAT, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that reducing insulin upregulates oxidative proteins in inguinal WAT without affecting Ucp1, while in mesenteric WAT and BAT, reducing insulin upregulates Ucp1 in the context of HFD. Preventing hyperinsulinemia has early depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1^+/- mice.

中文翻译：

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Ucp1或线粒体氧化复合蛋白的脂肪库特定上调是小鼠遗传胰岛素减少的早期后果。

高胰岛素血症在脂肪扩张中起因果作用。胰岛素减少的小鼠增加了能量消耗，但机理尚不清楚。我们调查了遗传减少胰岛素产生对肝脏，骨骼肌，白色脂肪组织（WAT）和棕色脂肪组织（BAT）中解偶联和氧化线粒体蛋白的影响。从8周龄开始，对雄性Ins1 ^{+ / +}或Ins1 ^+/-同窝幼仔进行低脂饮食（LFD）或高脂饮食（HFD）喂养4周。复制我们以前的观察结果，HFD增加了空腹高胰岛素血症，与Ins1 ^{+ / +}相比，Ins1 ^+/-小鼠的循环胰岛素明显降低同窝仔。不同基因型的空腹血糖和体重无差异。我们没有观察到骨骼肌肝脏的显着差异。在肠系膜WAT中，Ins1 ^+/-小鼠的Ndufb8和Sdhb减少。在HFD中，Ucp1升高，而单独的HFD对Pparg的丰度具有显着的抑制作用。在腹股沟WAT中，Ins1 ^+/-小鼠在不影响饮食的情况下，氧化复合蛋白显着增加，而不会影响Ucp1，Pparg或Prdm16：Pparg的结合。在BAT中，降低的胰岛素增加了HFD已降低的Sdhb蛋白水平。在缺乏饮食引起的高胰岛素血症的情况下，Ucp1蛋白，Prdm16：Pparg缔合和Sirt3丰度均增加。我们的数据显示，减少胰岛素会增加腹股沟WAT中的氧化蛋白而不影响Ucp1，而在肠系膜WAT和BAT中，减少胰岛素会在HFD中上调Ucp1。预防高胰岛素血症对脂肪组织的代谢具有早期的库房特效，并有助于解释先前在Ins1 ^+/-小鼠中报道的能量消耗增加。