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Regulation of Fat-Stimulated Neurotensin Secretion in Healthy Subjects

Clinical Research Centre (J.D., S.M., C.B.), Department of Research, and Division of Gastroenterology (S.M., C.B.) and Department of Clinical Pharmacology (J.D.), University Hospital Basel, CH-4031 Basel, Switzerland; and Rotta Pharma Spa (M.D.), 20052 Monza, Italy

Address all correspondence and requests for reprints to: Christoph Beglinger, M.D., Division of Gastroenterology, University Hospital, CH-4031 Basel, Switzerland. E-mail: beglinger{at}tmr.ch.

Context: Cholecystokinin (CCK) and neurotensin are stimulated during meal intake by the presence of fat in the small intestine. The sequence of events suggests that fat hydrolysis is crucial for triggering the release.

Objective: The aim of this study was to investigate whether CCK mediated the effect of intraduodenal (ID) fat on neurotensin secretion via CCK-1 receptors.

Setting: This was a single center study; 34 male volunteers were studied in consecutive, randomized, double-blind, cross-over studies.

Subjects and Methods: CCK and neurotensin release were quantified in: 1) 12 subjects receiving an ID fat infusion with or without 60 mg orlistat, an irreversible inhibitor of gastrointestinal lipases, in comparison to vehicle; 2) 12 subjects receiving ID long chain fatty acids (C18s), ID medium chain fatty acids, or ID vehicle; and 3) 10 subjects receiving ID C18 with and without the CCK-1 receptor antagonist dexloxiglumide or ID vehicle plus iv saline (placebo). Hormone concentrations were measured by specific RIA systems.

Results: ID fat induced a significant increase in CCK and neurotensin concentrations (P < 0.001–0.002). Inhibition of fat hydrolysis by orlistat abolished both effects. C18 stimulated CCK and neurotensin release (P < 0.001, respectively), whereas medium chain fatty acid was ineffective. Dexloxiglumide administration partially blocked the effect of C18 on neurotensin; the effect was only present in the first phase of neurotensin secretion.

Conclusions: Generation of C18 through hydrolysis of fat is a critical step for fat-induced stimulation of neurotensin in humans; the signal is in part mediated via CCK release and CCK-1 receptors.