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Title: The role of leptin receptors in the endocrine pancreas and nucleus tractus solitarius
Author: Soedling, Helen
ISNI:       0000 0004 7655 3154
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2018
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The highly controlled regulation of pancreatic hormone secretion is vital to keep the body’s glucose concentration at a constant level. Defects in the regulation of glucose levels are involved in several metabolic diseases, including type 2 diabetes and obesity. Leptin is a satiety hormone with important roles in the maintenance of body weight and glucose homeostasis. Mice that lack leptin (ob/ob) or the leptin receptor (db/db) are massively obese and have diabetes symptoms. Leptin has been demonstrated to have an effect on glucose homeostasis that is suggested to be secondary to the obesity these animals are suffering from. Currently, it is unclear how leptin regulates glucose homeostasis. Leptin mediates its effects by interaction with its leptin receptor (LepRb), which is highly expressed in the hypothalamus, and at lower levels in the periphery. Leptin’s effect on glucose homeostasis has been proposed to be mediated via its receptor expressed on pancreatic cells affecting insulin secretion. Previous animal studies have deleted the leptin receptor in pancreatic β- and α-cells using either “leaky” or inefficient Cre-drivers resulting in conflicting results on glucose homeostasis. In this study, we use a β-cell selective Ins1Cre promoter in mice to investigate the role of leptin receptor expressed on pancreatic cells effect on glucose homeostasis. Deletion of LepRb was found to have minor effects on glucose tolerance in female animals an effect that was only detected in 8 weeks old animals. No effect was observed in male animals or in females above the age of 8 weeks. It is well established that the LepRb in hypothalamus plays an important role in regulation of energy balance. However, the LepRb is expressed in several areas outside hypothalamus, such as the nucleus of the solitary tract (NTS). GLP-1-expressing neurons in this area express the LepRb and it is therefore possible that these neurons mediate an effect on energy homeostasis or glucose homeostasis. We have therefore deleted LepRb in GLP-1 expressing neurons with a proglucagon specific promoter iGluCre. In this study, we found no effect on body weight or glucose homeostasis in animals deleted for LepRb in GLP-1 expressing neurons. Hypothalamus is the brain region that plays a key role in the regulation of feeding and energy homeostasis. This area contains anorexigenic and orexigenic neurons and intermingled with these neurons are subpopulation of neurons named RIP2Cre neurons expressing insulin. Due to the neurons location in the feeding area of the brain they are most likely having a role in energy homeostasis. Previous studies have suggested that tumour suppressor LKB1 plays a role on body weight and food intake in these neurons. Therefore, we deleted LKB1 selectively in the RIP2Cre neurons but failed to see a difference in body weight.
Supervisor: Rutter, Guy Sponsor: Medical Research Council ; Innovative Medicines Initiative for Diabetes ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral