title: Roles of dorsomedial hypothalamic cholecystokinin signaling in the controls of meal patterns and glucose homeostasis.
abstract: A role for dorsomedial hypothalamus (DMH) cholecystokinin (CCK) signaling in feeding control has been proposed. Administration of CCK into the DMH reduces food intake and OLETF rats lacking CCK1 receptors (CCK1R) become hyperphagic and obese. We hypothesized that site specific replenishment of CCK1R in the DMH of OLETF rats would attenuate aspects of their feeding deficits. Recombinant vectors of adeno-associated viral (AAV)-mediated expression of CCK1R (AAVCCK1R) were bilaterally delivered into the DMH of OLETF. OLETF rats with AAVCCK1R injections demonstrated a 65% replenishment of Cck1r mRNA expression in the DMH relative to lean LETO control rats. Although this level of replenishment did not significantly affect overall food intake or body weight through 14 weeks following viral injections, meal patterns were partially normalized in OLETF rats receiving AAVCCK1R with a significant decrease in dark cycle meal size and a small but significant decrease in daily food intake in the meal analysis chambers. Importantly, the elevation in blood glucose level of OLETF rats was attenuated by the AAVCCK1R injections (p=0.03), suggesting a role for DMH CCK signaling in glucose homeostasis. In support of this role, administration of CCK into the DMH of intact rats enhanced glucose tolerance, as this occurred through activation of CCK1R but not CCK2R signaling. In conclusion, partial replenishment of CCK1R in the DMH of OLETF rats, although insufficient for altering overall food intake and body weight, normalizes meal pattern changes and reduces blood glucose levels. Our study also shows a novel role of DMH CCK signaling in glucose homeostasis.
authors.affiliation: Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, 710061, China.
authors.forename: Guangjing
authors.initials: G
authors.lastname: Zhu
authors.forename: Jianqun
authors.initials: J
authors.lastname: Yan
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002766:Cholecystokinin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D011949:Receptors, Cholecystokinin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D001786:Blood Glucose; D012333:RNA, Messenger; D011949:Receptors, Cholecystokinin; D049452:Green Fluorescent Proteins; D002766:Cholecystokinin; D005947:Glucose