ABSTRACT
Apolipoprotein AIV (Apo AIV) and cholecystokinin (CCK) are secreted in response to fat consumption, and both cause satiation via CCK 1 receptor (CCK-1R)-containing vagal afferent nerves to the nucleus of the solitary tract (NTS), where Apo AIV is also synthesized. Fasted male Long-Evans rats received ip CCK-8 or fourth-ventricular (i4vt) Apo AIV alone or in combination. Food intake and c-Fos proteins (a product of the c-Fos immediate-early gene) were assessed. i4vt Apo AIV and/or ip CCK at effective doses reduced food intake and activated c-Fos proteins in the NTS and hypothalamic arcuate nucleus and paraventricular nucleus. Blockade of the CCK-1R by i4vt lorglumide adjacent to the NTS attenuated the satiating and c-Fos-stimulating effects of CCK and Apo AIV, alone or in combination. Maintenance on a high-fat diet (HFD) for 10 weeks resulted in weight gain and attenuation of both the behavioral and c-Fos responses to a greater extent than occurred in low-fat diet-fed and pair-fed HFD animals. These observations suggest that NTS Apo AIV or/and peripheral CCK requires vagal CCK-1R signaling to elicit satiation and that maintenance on a HFD reduces the satiating capacity of these 2 signals.
Subject(s)
Apolipoproteins A/metabolism , Appetite Regulation , Cholecystokinin/metabolism , Nerve Tissue Proteins/metabolism , Neurons, Afferent/metabolism , Receptor, Cholecystokinin A/metabolism , Solitary Nucleus/metabolism , Animals , Apolipoproteins A/administration & dosage , Apolipoproteins A/genetics , Apolipoproteins A/pharmacology , Appetite Depressants/administration & dosage , Appetite Depressants/pharmacology , Appetite Depressants/therapeutic use , Appetite Regulation/drug effects , Appetite Stimulants/administration & dosage , Appetite Stimulants/pharmacology , Appetitive Behavior/drug effects , Behavior, Animal/drug effects , Cholecystokinin/administration & dosage , Cholecystokinin/analogs & derivatives , Cholecystokinin/antagonists & inhibitors , Diet, High-Fat/adverse effects , Hormone Antagonists/administration & dosage , Hormone Antagonists/pharmacology , Infusions, Intraventricular , Injections, Intraperitoneal , Male , Nerve Tissue Proteins/administration & dosage , Nerve Tissue Proteins/agonists , Nerve Tissue Proteins/antagonists & inhibitors , Neurons, Afferent/drug effects , Obesity/drug therapy , Obesity/etiology , Obesity/metabolism , Rats , Rats, Long-Evans , Receptor, Cholecystokinin A/agonists , Receptor, Cholecystokinin A/antagonists & inhibitors , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Sincalide/administration & dosage , Sincalide/analogs & derivatives , Sincalide/pharmacology , Solitary Nucleus/drug effectsABSTRACT
Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are gastrointestinal satiation signals that are stimulated by fat consumption. Previous studies have demonstrated that peripheral apo AIV cannot cross the blood-brain barrier. In the present study, we hypothesized that peripheral apo AIV uses a CCK-dependent system and intact vagal nerves to relay its satiation signal to the hindbrain. To test this hypothesis, CCK-knockout (CCK-KO) mice and Long-Evan rats that had undergone subdiaphragmatic vagal deafferentation (SDA) were used. Intraperitoneal administration of apo AIV at 100 or 200 µg/kg suppressed food intake of wild-type (WT) mice at 30, 60, and 90 min. In contrast, the same dose did not reduce food intake in the CCK-KO mice. Blockade of the CCK 1 receptor by lorglumide, a CCK 1 receptor antagonist, attenuated apo AIV-induced satiation. Apo AIV at 100 µg/kg reduced food intake in SHAM rats but not in SDA rats. Furthermore, apo AIV elicited an increase in c-Fos-positive cells in the nucleus of the solitary tract (NTS), area postrema, dorsal motor nucleus of the vagus, and adjacent areas of WT mice but elicited only an attenuated increase in these same regions in CCK-KO mice. Apo AIV-induced c-Fos positive cells in the NTS and area postrema of WT mice were reduced by lorglumide. Lastly, apo AIV increased c-Fos positive cells in the NTS of SHAM rats but not in SDA rats. These observations imply that peripheral apo AIV requires an intact CCK system and vagal afferents to activate neurons in the hindbrain to reduce food intake.
