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bioRxiv · 10.1101/2020.03.31.018432

Adipocyte depot-specific up-regulation of uncoupling protein 1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Botezelli, J. D.·Overby, P.·Lindo, L.·Wang, S. D.·Haida, O.·Lim, G. E.·Templeman, N. M.·Pauli, J. R.·Johnson, J. D.
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Abstract

Hyperinsulinemia plays a causal role in adipose tissue expansion. Mice with reduced insulin have increased energy expenditure, but the mechanisms remained unclear. Here 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.

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Botezelli, J. D., Overby, P., Lindo, L., Wang, S. D., Haida, O., Lim, G. E., Templeman, N. M., Pauli, J. R., Johnson, J. D.. 2020-04-01. Adipocyte depot-specific up-regulation of uncoupling protein 1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice. https://doi.org/10.1101/2020.03.31.018432

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