Nesfatin-1 and Nucleobindin Peptides in Energy Regulation

Nesfatin-1 is a potent anorexigenic peptide derived from the precursor protein nucleobindin-2 (NUCB2). Widely expressed in hypothalamic nuclei, brainstem centres and peripheral tissues such as liver and adipose, nesfatin-1 orchestrates feeding behaviour, glucose homeostasis and lipid metabolism. Upon proteolytic processing by prohormone convertases, distinct fragments of NUCB2—nesfatin-1, ‑2 and ‑3—acquire specialised conformations that determine receptor engagement and bioactivity. Central actions of nesfatin-1 engage the AMPK–ACC pathway to stimulate fatty-acid oxidation and inhibit lipogenesis, while peripheral effects modulate insulin secretion and GLUT4 translocation via AKT phosphorylation. A related peptide processed from nucleobindin-1 also attenuates hepatocyte lipid accumulation through AMPK activation, underscoring a broader family of nucleobindin-derived regulators. Structural modulation by zinc ions further fine-tunes the exposure of core anorexigenic motifs, suggesting a spatiotemporal control of peptide availability. The integration of nesfatin-1 signalling with key metabolic sensors highlights its global significance in energy homeostasis and positions nucleobindin peptides as promising targets for interventions in obesity, diabetes and lipid disorders.

Research from Nature Portfolio

Recent studies have demonstrated that both nesfatin-1 and a related peptide processed from nucleobindin-1 markedly reduce hepatic lipid accumulation in cultured hepatocytes by down-regulating lipogenic enzyme transcripts and up-regulating β-oxidation genes. The lipid-lowering effects are mediated through AMPK activation, as pharmacological inhibition of AMPK abolishes the response. Genetic deletion of the nucleobindin-1 gene in mice alters hepatic expression of lipid metabolism-associated genes, reduces endogenous nucleobindin-2 mRNA levels and diminishes AMPK phosphorylation, confirming the integral role of nucleobindin-derived peptides in metabolic control. A foundational study further revealed that central administration of nesfatin-1 modulates hypothalamic gonadotrophin and kisspeptin gene expression, suggesting that nesfatin-1 integrates energy status with neuroendocrine axes and emphasising its systemic importance.

Nesfatin-1 and Nucleobindin Peptides in Energy Regulation publication trend

The graph below shows the total number of articles in nesfatin-1 and nucleobindin peptides in energy regulation across all publications each year (not limited to Nature Index journals).

Technical terms

Nesfatin-1: An anorexigenic peptide processed from nucleobindin-2 that suppresses appetite and regulates energy homeostasis.

Nucleobindin-2 (NUCB2): A calcium-binding precursor protein that is proteolytically cleaved to generate nesfatin-1, ‑2 and ‑3.

Anorexigenic: Describing a substance that inhibits appetite.

AMPK (AMP-activated protein kinase): A cellular energy sensor that activates catabolic pathways and inhibits anabolic processes.

mTORC1 (mechanistic target of rapamycin complex 1): A nutrient-sensitive kinase complex that regulates lipid synthesis and cell growth.

β-oxidation: The mitochondrial process of fatty acid breakdown to generate ATP.

References

1. Deciphering the dual nature of nesfatin-1: a tale of zinc ion’s Janus-faced influence. Cell Communication and Signaling (2024).
2. NUCB2/Nesfatin-1 drives breast cancer metastasis through the up-regulation of cholesterol synthesis via the mTORC1 pathway. Journal of Translational Medicine (2023).
3. Nesfatin-1 and nesfatin-1-like peptide attenuate hepatocyte lipid accumulation and nucleobindin-1 disruption modulates lipid metabolic pathways. Communications Biology (2024).
4. Nesfatin-1 Stimulates Fatty-Acid Oxidation by Activating AMP-Activated Protein Kinase in STZ-Induced Type 2 Diabetic Mice. PLOS ONE (2013).
5. Peripheral Effects of Nesfatin-1 on Glucose Homeostasis. PLOS ONE (2013).
6. Role of Nesfatin-1 in the Reproductive Axis of Male Rat. Scientific Reports (2016).