OB-RGRP, a negative regulator of the leptin receptor in mice, may become a new target for obesity treatment
A research team from the Institut Cochin directed by Dr. Ralf Jockers in close collaboration with three CNRS laboratories (UMR 8161, Yves Rouillé; UMR 8090, Philippe Froguel; UMR 7091, Jacques Mallet) presents new data indicating that the OB-RGRP protein may become a new target for obesity treatment. The study shows that OB-RGRP negatively regulates the function of the leptin receptor, the protein that regulates body weight and food intake. Indeed, silencing of OB-RGRP in neurons increases their leptin sensitivity. This observation is of major importance as most obese people are unfortunately insensitive (resistant) to leptin. Our study, which has been published in the November issue of the Proceedings of the National US Academy of Sciences (PNAS) shows that silencing of OB-RGRP in the hypothalamus of mice that have been fed with a high fat diet (equivalent to the “McDonalds” diet of our society) prevents the development of obesity in these mice.
Team: Physiopathology and regulation of hormonal receptors
OB-RGRP, a negative regulator of leptin receptor (OB-R) function
Obesity is a major public health problem of our modern society and is associated with the development of type 2 diabetes, cardio-vascular diseases and an increased risk of cancer development. Indeed, about 40% of French people are overweight and more than 12% are obese. Despite the fact that the level of obesity has already doubled within the last ten years, a further increase can be anticipated in the near future. Mexico, for example, has reached second place just behind the United States with almost 30% of its population being considered obese and 21% of its public health budget spend by the medical costs induced by this pandemic obesity.
Leptin is one of the key hormones that is involved in the sensation of satiety and the control of body weight and energy expenditure. Leptin targets specific receptors (OB-R) that are expressed in several peripheral tissues and the central nervous system, particularly in the hypothalamic arcuate nucleus (ARC), the region involved in body weight regulation. Leptin is predominantly secreted by the adipose tissue and its blood levels directly correlate with adipose tissue mass. In normal people, high leptin levels induce an increase in energy expenditure and a decrease in food intake, and thus a decrease of adipose tissue mass and circulating leptin levels. Paradoxically, this control mechanism does not function anymore in obese individuals and we are talking about a leptin resistance. The prevention of this resistance is one of the major goals of obesity research.
In 1997, our laboratory discovered that the gene encoding the leptin receptor (OB-R), the molecular target of leptin, generates a second transcript called OB-RGRP for "OB-R gene related protein" (1). In 2002 the group of Dr Rosine Haguenauer-Tsapis showed that Vps55p, the yeast homologue of OB-RGRP, regulates the protein transport from the Golgi to the vacuole (2). Inspired by this pioneering work, we postulated that OB-RGRP might have a similar function in humans and more specifically on OB-R due to their genetic linkage. Our work published this week in Proc. Natl. Acad. Sci (3) show that OB-RGRP regulates the intracellular transport of OB-R and that the inhibition of its expression significantly increases the number OB-R at the cell surface as well as the sensitivity of the cell to this hormone.
We applied this observation to the mouse model of diet-induced obesity that is accompanied with the development of leptin resistance. Silencing of OB-RGRP in the ARC by RNA interference prevented the development of obesity in treated mice that maintained a normal body weight in contrast to control mice. The RNA interference method, which has been awarded the Nobel Prize in “Physiology and Medicine” in 2006, is based on small RNA molecules that are able to silence the expression of a specific gene.
Our work provides several new perspectives for the treatment of obesity. We identified OB-RGRP as a new target and we are proposing a novel therapeutic concept, namely, the use of molecules that inhibit the action of negative regulators of hormone receptors instead of using molecules that directly target these receptors. Specific therapeutic applications may also be envisaged for the treatment of obesity and associated diseases such as type 2 diabetes. If the results obtained in the diet-induce obesity mouse model are transposable to humans, inhibition of OB-RGRP (either by RNA interference or by pharmacological antagonists) may allow a restoration of leptin sensitivity in obese individuals and contribute to their weight loss.
This work has been supported by grants from Aventis, le Programme National de Recherches sur le Diabète (PNRD) and an A.F.E.R.O. fellowship.
Sources
(1) Bailleul, B, Akerblom, I & Strosberg, AD (1997) Nucleic Acids Res 25: 2752-8.
(2) Belgareh-Touze, N, Avaro, S, Rouille, Y, Hoflack, B & Haguenauer-Tsapis, R (2002) Mol Biol Cell 13: 1694-1708.
(3) “Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signalling and prevents diet-induced obesity”
Couturier C, Sarkis C, Séron K, Belouzard S, Chen P, Lenain A, Corset L, Dam J, Vauthier V, Dubart-Kupperschmitt A, Mallet J, Froguel P, Rouillé Y, Jockers R
(2007) Proc Natl Acad Sci
Contact
Ralf Jockers
Directeur de recherche Inserm
Institut Cochin
Tel.: 01 40 51 64 34
jockers@cochin.inserm.fr