Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects.

Autor: Asker M; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.; Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden., Krieger JP; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden., Liles A; Department of Chemistry, Syracuse University, Syracuse, New York, USA., Tinsley IC; Department of Chemistry, Syracuse University, Syracuse, New York, USA., Borner T; Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Maric I; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.; Department of Chemistry, Syracuse University, Syracuse, New York, USA.; Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA., Doebley S; Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA., Furst CD; Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA., Börchers S; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.; Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden., Longo F; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden., Bhat YR; Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA., De Jonghe BC; Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Hayes MR; Department of Biobehavioral Health Sciences, University of Pennsylvania, School of Nursing, Philadelphia, Pennsylvania, USA.; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Doyle RP; Department of Chemistry, Syracuse University, Syracuse, New York, USA.; Departments of Medicine and Pharmacology, State University of New York, Upstate Medical University, Syracuse, New York, USA., Skibicka KP; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.; Wallenberg Centre for molecular and translational medicine, University of Gothenburg, Gothenburg, Sweden.; Department of Nutritional Sciences, Pennsylvania State University, University Park, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: Diabetes, obesity & metabolism [Diabetes Obes Metab] 2023 Mar; Vol. 25 (3), pp. 856-877. Date of Electronic Publication: 2023 Jan 09.
DOI: 10.1111/dom.14937
Abstrakt: Objectives: Oxytocin (OT) has a well-established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT-R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT-R activation is sufficient to alter energy intake and expenditure.
Methods and Results: We first show that systemic OT potently reduced food intake and food-motivated behaviour for a high-fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood-brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled-OT (fAF546-OT, Roxy), for the presence of IP-injected Roxy in CNS tissue relevant to feeding control and compared such with BBB-impermeable fluorescent OT-B 12 (fCy5-OT-B 12; BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT-R, we generated a novel BBB-impermeable OT (OT-B 12 ), with equipotent binding at OT-R in vitro. In vivo, IP-injected OT and OT-B 12 were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT-R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT-B 12 did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose-dependent reduction of emesis in male shrews. While both OT and OT-B 12 proved to have similar effects on body temperature, only OT resulted in home-cage locomotor depression.
Conclusions: Together our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT-R may be a viable strategy to achieve appetite suppression with better patient outcomes.
(© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz: