Role of endozepines in the central regulation of normal and pathological energetic metabolism – EZICROM
Obesity, insulin resistance, and type-2 diabetes (T2D) are growing health concerns, and the incidence and prevalence of these diseases are increasing worldwide. Beside dietary treatment, the current therapeutic strategies consist of 2 main types of products: those dealing with complications of obesity such as anti-diabetic or anti-cholesterol, and those altering the feeding behavior such as appetite suppressants. Among these, anorexigenic molecules derived from amphetamine and fenfluramine were recently banned from prescription because of side effects, reducing the potential for pharmacological treatment of obesity. While the availability of novel drugs, techniques, and surgical intervention has improved the survival rate of individuals with diabetes, its prevalence still rises. These alarming statistics underscore the need for research aimed at discovering novel therapeutic strategies for the prevention or treatment of these diseases. Thus, the need for a better understanding of how glucose homeostasis is regulated is compelling; as such information is essential to develop new strategies for safe and effective treatments for obesity and T2D. In this context, it is now well established that some neuropeptides play a key role in the control of food intake. In particular, neurons in the arcuate nucleus of the hypothalamus that express NPY and those that synthesize a-MSH exert opposite effects on food intake. Partner 1 has previously demonstrated that central administration of the gliopeptide ODN, belonging to the endozepines family, causes a dramatic decrease in food intake combined with an irreversible loss of body weight. In line with recent advances in neuron-glia communication showing that glia is involved in the detection of various physiological parameters, we hypothesize that glial cells bordering the 3rd and the 4th ventricles (tanycytes and vagliocytes) are able to sense the local glycemia to inform the hypothalamus and the dorsal vagal complex (DVC) on systemic glucose homeostasis by using ODN signalling. Preliminary results from Partner 2 show that local injection of ODN-isoactive fragment in the 4th ventricle decreases food intake. Moreover, injection of the same peptide in the 3rd ventricle prevents fasting-mediated plasticity of the tanycytic barrier suggesting that ODN signaling modulates the exchanges between the hypothalamus and the CSF (preliminary data, Partner 3). Collectively, our present results converge to the view that ODN is the key-factor of a novel feedback loop controlling whole-body glucose homeostasis. This project represents an integrated approach towards understanding the mechanisms of the gliopeptide signaling in the CNS in order to contribute to innovative therapies for the treatment of obesity and/or diabetes. The multidisciplinary approach of the project will lead to significant advances at the junction of three fields: i) the ODN system, ii) the glio-neuronal communication and iii) the regulation of glucose homeostasis. The consortium federates the efforts of 3 internationally recognized teams strongly involved on these concepts. Partner 1, Inserm U982 (Rouen), has an international reputation in the field of neuropeptides, neuroendocrinology and neuroscience, Partner 2, PPSN (ex UMR 6231, Marseille), is a new team with an international reputation in autonomic neuroscience, feeding behavior and glucose sensing and Partner 3, Inserm U1172 (Lille), has an international expertise in the impact of peripheral hormones on hypothalamic development and function. The combination of the 3 partner’s skills will provide a research framework going from molecular neurobiology to animal models with potential output to human clinic. Their researches will shed light on novel pathway of glucose sensing in the brain and could therefore possibly lead to identification of novel targets for the treatment of metabolic disorders.
Monsieur Jérôme LEPRINCE (Différenciation et Communication Neuronale et Neuroendocrine)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Inserm U982 Différenciation et Communication Neuronale et Neuroendocrine
PPSN (EA4674) Physiologie et Physiopathologie du Systeme Nerveux
Inserm U1172 Développement et Plasticité du Cerveau Postnatal
Help of the ANR 605,572 euros
Beginning and duration of the scientific project: September 2016 - 36 Months