Nesfatin-1: a novel inhibitory regulator of food intake and body weight

Abstract

The protein nucleobindin 2 (NUCB2) or NEFA (DNA binding/EF-hand/acidic amino acid rich region) was identified over a decade ago and implicated in intracellular processes. New developments came with the report that post-translational processing of hypothalamic NUCB2 may result in nesfatin-1, nesfatin-2 and nesfatin-3 and convergent studies showing that nesfatin-1 and full length NUCB2 injected in the brain potently inhibit the dark phase food intake in rodents including leptin receptor deficient Zucker rats. Nesfatin-1 also reduces body weight gain, suggesting a role as a new anorexigenic factor and modulator of energy balance. In light of the obesity epidemic and its associated diseases, underlying new mechanisms regulating food intake may be promising targets in the drug treatment of obese patients particularly as the vast majority of them display reduced leptin sensitivity or leptin resistance while nesfatin-1's mechanism of action is leptin independent. Although much progress on the localization of NUCB2/nesfatin-1 in the brain and periphery as well as on the understanding of nesfatin-1's anorexic effect have been achieved during the past three years, several important mechanisms have yet to be unraveled such as the identification of the nesfatin-1 receptor and the regulation of NUCB2 processing and nesfatin-1 release.

Figure 1

Potential pathways by which nesfatin-1 induces a sustained and prolonged reduction of dark phase food intake and delays gastric emptying in rats as suggested by pharmacological interventions and neuroanatomical approaches. Central nesfatin-1/NUCB2 mediates its anorexigenic effect via activation of melanocortin_3/4 and CRF₂ signalling and also by hyperpolarizing neurons containing the orexigenic peptide, neuropeptide Y. Nesfatin-1 also activates the hypothalamic magnocellular oxytocinergic system which could reduce food intake and delay gastric emptying. Peripheral nesfatin-1 can reach the brain via the circulation and crossing the blood-brain barrier and/or direct action on circumventricular organs as well as modulation of vagal afferent activity. +, stimulation; −, inhibition; ↓, reduction; Arc, arcuate nucleus; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; PVN, paraventricular nucleus of the hypothalamus; SON, supraoptic nucleus (7,15,22,23,25).

Figure 2

Corticotropin-releasing factor receptor antagonists injected intracerebroventricularly (icv) prevent the icv nesfatin-1 induced reduction of dark phase food intake in freely fed rats (A). Chronically icv cannulated rats were injected with 30 µg rat⁻¹ of astressin-B astressin₂-B or astressin₂-B analog devoid of CRF₂ binding affinity (inactive peptide) or vehicle before icv nesfatin-1 (0.05 µg rat⁻¹) or vehicle; cumulative food intake was monitored for 6h. *P<0.02 and **P< 0.001 vs. vehicle/vehicle. CRF receptor antagonists injected intracisternally (ic) do not prevent the ic nesfatin-1 induced reduction of dark phase food intake (B). Rats under brief anesthesia were injected ic with 30 µg rat⁻¹ of astressin-B, astressin₂-B or vehicle before ic injection of nesfatin-1 (0.5 µg rat⁻¹) or vehicle and cumulative food intake monitored for 6h. *P<0.05 and **P < 0.005 vs. vehicle/vehicle. Bars represent the mean ± SEM of number of rats indicated at the bottom. Reproduced with permission from reference (22); Copyright 2009, The Endocrine Society.