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Cell Rep. 2018 Jul 31;24(5):1085-1092.e6. doi: 10.1016/j.celrep.2018.06.112.

Loss of Nucleobindin-2 Causes Insulin Resistance in Obesity without Impacting Satiety or Adiposity.

Author information

1
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
2
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA.
3
Department of Genomics and Immunoregulation, LIMES Institute, University of Bonn, 53115 Bonn, Germany.
4
Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; The Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
5
Department of Genomics and Immunoregulation, LIMES Institute, University of Bonn, 53115 Bonn, Germany; Platform for Single Cell Genomics and Epigenomics, University of Bonn and the German Center for Neurodegenerative Diseases, Bonn, Germany.
6
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: vishwa.dixit@yale.edu.

Abstract

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:

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

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