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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - INTEGRATE (Central integration of metabolic and hedonic cues in metabolic health)

Teaser

The control of blood glucose levels and of feeding behavior depends on the activitiy of intricate brain neuronal circuits. Many of those have their activity directly controlled by the concentration of glucose in the blood - meaning that glucose is an important regulator of its...

Summary

The control of blood glucose levels and of feeding behavior depends on the activitiy of intricate brain neuronal circuits. Many of those have their activity directly controlled by the concentration of glucose in the blood - meaning that glucose is an important regulator of its own homeostasis and of feeding , in particular of motviated sugar-seeking and eating behavior. Deregulation of these central glucose sensing systems may lead to chronic diseases such as obesity and type 2 diabetes as well as bulimia or anorexia.

The goal of INTEGRATE is identify glucose sensing neuronal population that are activated by rise in glucose concentations (glucose excited or GE neurons) or by development of hypoglycemia (glucose inhibited or GI neurons) and to characterize the neuronal circuit they are invilved in and the physiological functions they control.

The importance of this work lies in the fact that these neuronal glucose-regulated systems are so far very poorly described and identifying them and understanding how they become deregulated in the pathogenesis of metabolic diseases may provide novel therapeutic means to prevent or treat these diseases.

Work performed

We have been working on two specific brain areas. One is the ventromedial hypothalamus (VMN), a region of the hypothalamus known to have multiple effects on the homeostatic (automatic) regulation of blood glucose concentrations and feeding behavior. This region contains neurons that are activated by glucose and an equal proportion that are activated by hypoglycemia. We have performed studies in mice to show that the activity of the hypoglycemia-activated GI neurons depends on the presence of a particular enzyme that is activated by hypoglycemia and leads to protein modifications by a mechanism called phosphorylation. In the absence of this enzyme, GI neurons are no longer active in the VMN. By gene expression analysis in the VMN of mice with inactivation of this enzyme we have now identified two potential effectors of this enzyme that are required for the normal activation of the GI neurons by hypoglycemia. One has been confirmed and my represent a novel regulator of hypoglycemia detection in the central nervous system.

The second brain area that we are investigating is the paraventricular thalamic area, a region of the thalamus that has many connections with the hypothalamus. However, this brain structure is also involved in the control of the hedonic and motivational aspects of feeding. We have characterized two populations of neurons in this region, one that express the glucose transporter Glut2 and which is activated by hypoglycemia (GI neurons). The other one express a another enzyme involved in glucose metabolism and these neurons are in large part activated by glucose (GE neurons). We found that, when activated, the GI neurons induce moticated sucrose seeking behavior whereas the GE neurons suppress feeding. We have thus uncovered a dual glucose sensing system in the thalamus that have control on both stimulation and inhibition of feeding.

Final results

We expect to progress our knowledge of the brain function in energy homeostasis alon several lines.
First, by discovering, at the molecular level, how hypoglycemia activates neurons. This will be the basis for a better understanding of the defect in hypoglycemia detection that is a frequent occurence in insulin treated diabetic patients.,
Second, by defining an intricate neuroanl regulatory network in the thalamus that responds to both hypoglycemia and hyperglycemia - conditions related to fasting and fed states - and which controls motivated sucrose seeking behavior. Deregulation of this mechanism may be associated with sugar craving and development of obesity, a risk factor for type 2 diabetes. Molecular analysis of the make up of these neuronal populations may lead to identification of molecular targets for the treatment of metabolic diseases.