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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., In Brief Obesity induces Nucb2 expression in adipose macrophages as an endogenous brake to restrain metabolic inflammation. Ravussin et al. show that ablation of Nucb2 globally or knockdown in orexigenic neurons and adipocytes did not affect food intake or adiposity. The loss of Nucb2 in myeloid cells drive inflammation and insulin resistance upon high-fat feeding., Graphical Abstract