Medical Research
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CB-1 Receptor/Rimonabant
I think this is important. Maybe really important.
The CB-1 receptor in the brain is the receptor that marijuana binds to. I have lifted this write up from a colleague (Norm Bauman) on a science writer's listserve and I will try and do my own soon:
"For good background, see the current Scientific American, Dec 2004, The Brain's own marijuana, Roger A. Nicoll and Bradley E. Alger. THC stimulates the CB1 receptor, whose natural ligands are 2 short fatty acids, anandamide and 2-arachidonyl glycerol (2-AG). 2-AG causes retrograde signaling at synapses. Normally, glutamate-transmitting neurons can fire a postsynaptic neuron. However, GABA-transmitting neurons can inhibit that signal. However, in response to calcium depolarization, the post-synaptic neuron can transmit 2-AG back to the presynaptic GABA-transmitting neuron, which stops the GABA transmission, stops the inhibition, and allows the post-synaptic neuron to fire again in response to the glutamate. Dampening inhibition enhances long-term potentiation. Depolarized-induced suppression of inhibition "enables individual neurons to disconnect briefly from their neighbors and encode information."
If CB1 knockout mice are conditioned to a sound followed by an electric shock, they are unable to experience extinction after the sound and shock are uncoupled. "Endocannabinoids are important in extinguishing the bad feelings and pain triggered by reminders of past experiences."
Anatomy: Cannabinoid receptors in the hypothalamus are involved in appetite, hormones and sexual behavior; in the basal ganglia, in planning, initiation and termination of action; in the cerebellum, in motor control; in the neocortex, in higher cognitive functions and integration of sensory information; in the hippocampus, in memory and learning of facts, sequences and place; in the brain stem and spinal cord, in vomiting reflex and pain."
Me again: You may have seen posts on this list about an obesity drug that is currently in phase 3 trials called rimonabant. It is made by Sanofi-Synthelabo. It binds to this receptor. I am trying to stir up interest on CB-1 and PWS with CB-1 researchers. I can find nothing on CB-1 and PWS on Medline, but doesn't this receptor seem to hit a lot of the same problems or kids have? And, CB-1's natural ligand are two short fatty acids (fat metabolism??).
2002 International Symposium
I am currently reading the book Prader Willi Syndrome as a Model of Obesity edited by Eiholzer, l'allemand, and Zipf (available from Amazon). This is the summary of the 2002 International Symposium held in Zurich. It is expensive ($120), but well worth it if you like to read the science stuff.
Dr. Lee has an article in there where he proposes that the metabolic problem is not actually a problem with the hypothalamus, but rather is a problem in the periphery. I found his arguments quite convincing. "The peripheral model relies on disordered regulation of substrate- or tissue-generated signaling, an area which is even more poorly understood than central appetite regulation."
Also, some quotes from the Eiholzer article that I found interesting: "From this viewpoint, the onset of obesity represents the external manifestation of insufficient satiety and, at the same time, is an expression of increasing physical strength, health an the children's ability to get their way." (p.2) Does that make sense to any of you? Once the child becomes strong enough to eat well, then they keep eating and gaining weight?? "... children with PWS had decreased muscle mass in absolute terms (as opposed to children with nonsyndromal obesity, who had an increased muscle mass)..."
"Even after long-term growth hormone treatment, muscle mass remained distinctly decreased and fat mass was increased." While I doubt this sentence incorporates any data about infants given GH, it still underscores to me that while GH seems to be able to fix the problem (at least partly) it does not really get at the underlying cause.
In one spot he refers to hypoactivity as insufficient muscle mass. Does that mean that once our kids get enough muscle mass they become more active? Is there something wrong with their muscle or is it just that they don't have enough muscle? Is it a quality problem or just a quantity problem? Why are they low tone? Is it because their muscle to fat ratio is off? But that ratio stays off throughout their life and yet their tone improves with time.
Also, I've discussed PWS and diabetes and the value of a low glycemic index diet for our kids? Eiholzer writes: "The insulin levels, however, are low, at least in children and adolescents. In the periphery, insulin sensitivity is increased, in contrast to most individuals with non- syndromal obesity. Whether the low insulin levels centrally play a role in energy regulation is open."
Also, Eiholzer makes reference to daily training programs to augment GH therapy in the effort to achieve normal muscle mass. Does anyone know anything about this? He seems to discount it by saying: "The downside of a daily training programme, however, is that it requires an additional time investment on part of the parents and other caretakers."
Starvation or Obesity?
This interesting article argues that PWS is more a model of starvation than it is a model of obesity.
The paradox of Prader-Willi syndrome: a genetic model of starvation
Holland A, Whittington J, Hinton E.
Section of Developmental Psychiatry, Douglas House, CB2 2AH, Cambridge, UK. ajh1008@cam.ac.uk
The neurodevelopmental disorder, Prader-Willi syndrome, is generally regarded as a genetic model of obesity. Although the values of some hypothalamic neuropeptides are as expected in obesity, and should result in satiety, we propose that abnormal hypothalamic pathways mean that these are ineffective. We postulate that the body incorrectly interprets the absence of satiation as starvation, and therefore, paradoxically, this syndrome should be redefined as one of starvation that manifests as obesity in a food-rich environment. Also, this syndrome is generally believed to be a contiguous gene disorder, which results from the absence of expression of the paternally derived alleles of maternally imprinted genes on chromosome 15 (15q11-13). We argue, however, that the whole phenotype can be explained by one mechanism and, by implication, the failure of expression of the paternal allele of a single maternally imprinted gene that controls energy balance. We suggest clinical and laboratory approaches to test our hypotheses.
Purchase article] ($30)
Current studies
- Research on Behavior Differences When Related to Food University of North Carolina graduate student is conducting a parental survey-based research project on behavior differences between the three types of Prader-Willi syndrome when related to food versus non-food items. Your participation will be greatly appreciated!
- Genetics and Behavior: Compulsive Behavior in Prader-Willi Syndrome Researchers at the University of Kansas Medical Center and the Division of Genetics and Molecular Medicine at Children’s Mercy Hospital have embarked on a study to better understand compulsive behavior in individuals with Prader‑Willi syndrome (PWS).
- Research On Behavior And Development In Prader-Willi Syndrome Dr. Elisabeth Dykens. Seeking persons with Prader-Willi syndrome aged 4 years through adulthood, and their families to come participate at the Kennedy Center at Vanderbilt University in Nashville, TN.
- Understanding childhood obesity and specifically, the mechanism of development of obesity Andrea Haqq, MD, pediatric endocrinologist at Duke University Medical Center is conducting a study and needs your help.
- Summary of work being funded by the Foundation for Prader-Willi Research
- Appetite and Prader–Willi Syndrome B.C. Women's and Childrens Hospital Endocrinologist is studying the effect of somatostatin on levels of Ghrelin and appetite in persons with PWS. Your child must be 10–18 years of age and overweight to participate in this study. For further information about the trial, please contact Dr. Jean-Pierre Chanoine at 604-875-2624.
Other sites
- Research page from Prader-Willi Syndrome Association (PWSAUSA)
- Summary of work being funded by the Foundation for Prader-Willi Research
