Date: January 8th, 2009

Seminar Title: "Life without CCK receptors: New insights into central controls of food intake"

Speaker's Name and Affiliation:

• Timothy Moran
• Johns Hopkins University

Presiding Chair: Harry R. Kissileff, Ph.D.

Rapporteur: Kathleen L. Keller, Ph.D.

Attendees and their Affiliation:

Kathleen Keller	Columbia/Obesity Research Center
Harry Kissileff	Obesity Research Center
Allan Geliebter	Obesity Research Center
Barry Levin	NJ Medical School
Diane Klein	NYSPI/CU
Tony Sclafani	Brooklyn College
Karen Ackroff	Brooklyn College
Michael Lewis	Hunter
Michelle Lee	NYORC
Lori Zeltser	CUMC
Michael Devlin	CUMC/NYSPI
Susan Carnell	ORC
JA Grinker	University of Michigan
Katherine Halmi	Cornell
Ann-Marie Torregrossa	University of Utah
Gerry Smith	WMC-Cornell
Amy Samuelson	GSK
John Kral	SUNY Downstate
Carol Maggio	NYORC/St. Luke's
Joe Vasselli	NYORC

Summary: (Prepared by the Speaker)

Tim Moran presented an update on their work with the Otsuka Long Evans Tokushima Fatty (OLETF) Rat. The OLETF rat lacks CCK1 receptors, and consistent with this defect, does not respond to exogenous CCK and has meal patterns consistent with a satiety deficit - increased meal size. The OLETF rat does not compensate for this increase resulting in hyperphagia and obesity. Analyses of hypothalamic gene expression revealed increase dorsomedial hypothalamic (DMH) NPY in preobese OLETF rats and OLETF rats pair fed to amounts consumed by control rats. A role for this elevated NPY in the obesity is consistent with data demonstrating that DMH CCK injections reduce NPY mRNA expression and inhbit food intake in intake rats. Using adenoassociated viral (AAV) gene transfer techniques, it can be demonstrated that DMH NPY overexpression results in hypeprphagia and obesity mimicking aspects of the phenotype of OLETF rats and reducing DMH NPY expression in OLETF rats with AAV-RNAi rescues aspects of their phenotype, reducing food intake, body weight and normalizing meal patterns. These data support the role of DMH NPY dysregulation in the obesity syndrome of OLETF rats

Discussion:

Q. What about the meal size and frequency in the OLEFT rat at earlier ages?
A. Aron Weller has looked at meal sizes in animals as young as 3 days. Even at that age, these animals consumed larger meals.

Q. Are CCK-A receptors in the arcuate nucleus as well?
A. In the rat it is mainly CCK-B receptors in the arcuate nucleus..

Q. Do you know if leptin modulates DMH-NPY?
A. I'm getting to that next.

Q. If you deliver an antagonist that works peripherally but you deliver it into the ventricles of the brain, do you not see effects?
A. Yes that's correct.

Q. Are insulin receptors expressed in the DMH?
A. We haven't looked at that yet.

Q. What happens to meal frequency and rate?
A. Frequency drops, but not enough to normalize. We haven't looked at rate yet.

Q. What do we know about how NPY is being released? Is there more secreted from each of the vesicles.
A. I don't think we know that yet.

Q. Does the OLEFT rat show decreased satiating response to other gut hormones?
A. We looked at bombesin and GLP-1 and they were normal.

Q. Is there any evidence that overexpression of NPY is doing anything? Is that what is driving the animal to overeat?
A. I'm not sure. We were surprised by these data.

Q. Are there any CCK receptor knockouts in humans?
A. There is only one family. They are obese, but the main phenotype is that they all have gallstones.

Q. Since the OLEFT rat lacks CCK and overeats, could it be considered an animal model for binge eating?
A. The effects on food intake appear to constant for binge eating. Discrete binges are difficult to identify.

Q. So, is a criteria for binge eating disorder that the binges need to occur in discrete periods of time?
A. In a discrete period of time, but there is a lot of arbitrariness to it.

Q. Are there any steroid abnormalities in these animals?
A. Aron Weller is the only one studying this right now and he has permission to have a breeding colony. When the females become obese, it becomes hard for them to reproduce, so it's difficult to study.

Q. Is there a reduction in CCK release after gastric bypass surgery?
A. My guess is that it is altered, and likely goes down after gastric bypass.

Q. I've heard that there is an orally available CCK agonist?
A. Yes, and there was a 12-week study over a year ago that showed no effect.
Comment (H. Kissileff): We have down some work with the CCK agonist and we found some reductions in food intake with some doses.

Q. Does viral manipulation of DMH-NPY affect sweet perception?
A. I have no idea.

Q. How do you integrate these data with findings from Bernades and Belis (sp.). They show that DMH lesions decrease body weight set point.
A. I think our data generally agree with this.

Q. When a loss of eating control occurs, does CCK desensitize?
A. We don't have a good definition of a "loss of control."

Q. Does the OLEFT rat bar press for more food?
A. Yes

Q. What about fat? Do OLEFT rats prefer fat?
A. If given a choice, yes they prefer fat.