Five years ago, the protein Nucleobindin2 (NUCB2; Barnikol-Watanabe et al., 1994) was first suggested as a regulator of energy metabolism. Oh-I et al (2006) proposed that NUCB2 is cleaved into three protein fragments (nesfatin-1, -2 and -3) and showed that administration of nesfatin-1 into the brain results in anorexia and relative body weight loss. Mapping of NUCB2 in the brain revealed expression in several key metabolic control regions of the brain, including nuclei controlling feeding behaviour, but also endocrine and autonomic output, suggesting a role also in energy expenditure (Foo et al., 2008). Anatomical and biochemical data, however, are difficult to reconcile with processing of NUCB2 into fragments and secretion: NUCB2 immunoreactivity is consistently confined to cell bodies and absent from terminals, whereas western blot analysis to date has not revealed the existence of endogenous fragments corresponding to nesfatin-1. There is considerable overlap between the signal molecule repertoire between the metabolic regulatory regions of the CNS and peripheral organs involved in energy balance. Recent work from several groups, including ours (Gonzalez et al., 2009; Stengel et al., 2009; Foo et al., 2010), has shown that this is true for NUCB2, which shows particular concentration in the insulin-producing beta cells of the human and rodent pancreas (but is absent from other islet cells). While fasting did not affect NUCB2 islet content, it was decreased by 50% in islets from Goto-Kakizaki (GK) rats, a model of type 2 diabetes. Curiously, levels in the GJ islets normalized with fasting. Release of NUCB2 from islets following glucose challenge (+23%) were, however, modest compared to the increase in insulin secretion (+716%), arguing against a major secretory role for NUCB2 in islets. These and other data suggest that NUCB2 plays a role in the regulation of energy metabolism across several glucoregulatory organs, but that this role may be exerted intracellularly, rather than as a cleaved and secreted messenger.