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Unraveling the mechanism underlying the anti-diabetic action of leptin

Final Report Summary - LEPTINT1DM (Unraveling the mechanism underlying the anti-diabetic action of leptin)

Summary description of the project objectives:
The main objective of the project is to determine whether leptin action on POMC neurons is required and/or sufficient for leptin’s anti-type 1 diabetic action in mice.

Description of the work:
To determine whether leptin action on POMC neurons is required and/or sufficient for leptin’s anti-type 1 diabetic action in mice, we generated mice lacking or expressing leptin receptors only in POMC neurons. Pancreatic insulin-producing beta-cells were destroyed rendering these mutants type 1 diabetic. Intracranial administration of leptin was then achieved and clinical symptoms of type 1 diabetes monitored over time.

Description of the main results achieved:
The hyperglycemia-lowering action of leptin administration was partially blunted in type 1 diabetic mice lacking leptin receptors only in POMC neurons. On the other hand, the hyperglycemia-lowering action of leptin administration was completely abolished in type 1 diabetic mice expressing leptin receptors only in POMC neurons.

Expected final results and their potential impact and use (including the socio-economic impact and the wider societal implications of the project so far):

Leptin receptors on POMC neurons play a minor role for leptin’s anti-type 1 diabetic action. Thus leptin action on other non-POMC neurons exerts a major role for leptin’s anti-type 1 diabetic effect. Understanding the neuronal and molecular mechanisms underlying leptin action in type 1 diabetes will identify new molecular targets for counteracting the metabolic dysfunctions caused by insulin deficiency. Hence, these studies have the potential to significantly improve diabetes care.