Cell Reports
Volume 24, Issue 5, 31 July 2018, Pages 1085-1092.e6
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Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity

https://doi.org/10.1016/j.celrep.2018.06.112Get rights and content
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Highlights

  • Ablation of Nucb2 does not control food intake and adiposity

  • Loss of Nucb2 increases inflammation and insulin resistance

  • Nucb2 does not induce leukocytosis in obesity

  • Macrophage-expressed Nucb2 drives insulin resistance

Summary

Inducers of satiety are drug targets for weight loss to mitigate obesity-associated diseases. Nucleobindin-2 (Nucb2) is thought to be post-translationally processed into bioactive nesfatin-1 peptide, which reportedly induces satiety, causes weight loss, and thus improves insulin sensitivity. Here, we show that deletion of Nucb2 did not affect food intake or adiposity and, instead, caused insulin resistance in mice fed a high-fat diet. In addition, ablation of Nucb2 in orexigenic hypothalamic Agrp neurons did not affect food intake, and nesfatin-1 was detectable in serum, despite global deletion of Nucb2 protein. Upon high-fat diet feeding, the loss of Nucb2 exacerbated metabolic inflammation in adipose tissue macrophages in an NFκB-dependent manner without inducing classical M1 or alternative M2-like macrophage polarization. Furthermore, the loss of Nucb2 in myeloid cells but not in adipocytes mediated the insulin resistance in response to a high-fat diet. Our study reveals that Nucb2 links metabolic inflammation to insulin resistance without affecting weight gain and food intake.

Keywords

Nucb2
adipose tissue macrophage
inflammation
food intake
insulin sensitivity
immunometabolism
AgRP
adiponectin
nesfatin
hypothalamus

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