The neuropeptide 26RFa: a key player in the central regulation of glucose homeostasis, new therapeutic perspectives for Type 2 Diabetes? – DIABNET

Obesity and type 2 diabetes (T2DM) are strongly associated pathologies and are considered by the World Health Organization as an epidemic worldwide issue. Current treatments for T2DM, targeting the peripheral action of insulin, do not always succeed in balancing patients' diabetes. It is therefore becoming urgent to identify new therapeutic strategies for the prevention or treatment of these diseases. The hypothalamus plays a crucial role in both the control of feeding behavior and the regulation of glucose homeostasis, and the neuropeptidergic systems controlling these two neuroendocrine regulations partially overlap. Thus, a new concept has emerged, proposing that the pathogenesis of obesity and T2DM may originate from defects of the neuropeptidergic systems controlling both energy and glucose homeostasis in the hypothalamus. However, the molecular identity of these hypothalamic neuropeptidergic neuronal networks remains poorly known. In this context, the 26RFa/GPR103 neuropeptidergic system is of particular interest as it is expressed in hypothalamic nuclei involved in the control of energy balance. 26RFa exerts a robust orexigenic activity and is an important regulator of glucose homeostasis at the periphery via its sustained incretin activity. Altogether, these observations lead us to propose the present project that has two main objectives: 1/ to decipher the organization of the 26RFa/GPR103 system within the hypothalamic neuronal network regulating glucose homeostasis. 2/ to determine how this 26RFa/GPR103 neuronal network is involved in the onset of obesity/diabetes.
To reach these two ambitious aims, the present project will answer the following questions:
• What is the molecular identity of the 26RFa neurons in the hypothalamus and the distribution of 26RFa-containing fibers?
• What is the impact of modulating the 26RFa peptidergic system on the hypothalamic regulation of glucose homeostasis in healthy or obese/diabetic context?
• Is the 26RFa/GPR103 system a relay for the central regulation of glucose homeostasis by insulin?
• What are the downstream mechanisms that relay 26RFa signaling? Are they impaired in obese/diabetic mice?
Achievement of this project is based on the development of DREADD techniques for the first time in the laboratory, to specifically modulate the activity of the 26RFa-expressing neurons and the construction of Tomato-CRE reporter mouse lines. It represents an original chemogenetic approach to decipher the organization and understand the precise role of the 26RFa/GPR103 neuronal network in the central regulation of glucose homeostasis.
The recent data obtained by Dr Marie Picot strongly justify the interest of this proposal as they show that:
• A central administration of 26RFa improves glucose tolerance and insulin production.
• The central anti-hyperglycemic effect of 26RFa is abolished in the presence of a GPR103 antagonist and 26RFa mutant mice.
• The central hypoglycemic effect of insulin is partially blocked by a GPR103 antagonist and abolished in 26RFa mutant mice.
• Insulin strongly stimulates 26RFa secretion by the hypothalamus.
• 26RFa hypothalamic neurons express the insulin receptor and are activated by insulin.
These original and exciting data support the concept that the 26RFa/GPR103 hypothalamic system is involved in the neuronal network regulating glucose homeostasis and may be a relay of insulin in the brain and, thus, may represent a therapeutic target for the treatment of obesity/T2DM. In this context, this project explores a totally original field of research since, despite the challenges they represent in the fight T2DM, the central mechanisms of action of insulin are still very poorly understood. M. Picot's scientific and technical expertise is a major asset in i/ implementing innovative techniques, for the first time in the laboratory, ii/ lifting the scientific lock that the central mechanisms of action of insulin still represent today.