Abstract
BACKGROUND: Pro-neurotensin (pro-NT) is the stable circulating precursor of neurotensin (NT), a neuropeptide expressed mainly in the central nervous system and small intestine that regulates key physiological processes like fatty acid absorption in the gut and suppresses appetite via central mechanisms. Studies in NT-deficient mice and humans implicate NT in obesity and insulin resistance, highlighting its role in metabolic regulation. METHODS: To explore the genetic determinants of circulating pro-NT and its causal relationships with obesity and brain phenotypes, we conducted a genome-wide meta-analysis of serum pro-NT levels in 10,096 individuals of European ancestry across four independent cohorts. We further examined causal effects of pro-NT on brain structures and function using Mendelian Randomisation (MR) and analysed brain magnetic resonance imaging (MRI) data from a subset (N = 1090) of the LIFE-Adult cohort. FINDINGS: Three genome-wide significant loci associated with serum pro-NT were identified on chromosomes 4 (rs6822751), 11 (rs41392245), and 12 (rs2723889). MR analyses revealed causal links between elevated pro-NT and structural variation in selected subcortical brain regions, notably the pallidum and brainstem. MRI analyses in the LIFE-Adult subset showed reduced reward network coherence in alleles linked to higher pro-NT levels, suggesting a potential neural mechanism contributing to obesity. INTERPRETATION: These findings suggest a potential causal relationship between serum pro-NT levels and variance in structural brain phenotypes that could be implicated in obesity. FUNDING: See Acknowledgements. Key funding bodies: Deutsches Zentrum für Diabetesforschung (DZD, Grant: 82DZD06D03) to MSt; European Union, by the European Regional Development Fund (ERDF) to RB; Swedish Foundation for Strategic Research (IRC LUDC), Swedish Research Council (SFO-EXODIAB), Swedish Research Council (AIR Lund- Artificially Intelligent use of Registers at Lund University, VR; Grant No. 2019-61406) to OM.