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The effects of leptin knockout and insulin suppression on glucose metabolism in rodents

University of British Columbia

Background: The adipose-derived hormone leptin is well known for its effects on metabolic homeostasis, and in particular its role in suppressing appetite and regulating fat mass. Loss of leptin results in a phenotype characterized by obesity, insulin resistance, hyperinsulinemia and glucose intolerance. Treating leptin deficient mice with leptin is able to lower blood glucose and insulin levels without reducing body weight, indicating that leptin has independent effects on glucose homeostasis. While there have been many studies exploring the role of leptin in metabolism, the glucoregulatory actions of leptin remain to be fully elucidated. Scope of Thesis: The overall goal of this thesis was to understand the role of leptin in glucose regulation. To do so, we utilized a number of in vivo models in which leptin signalling was disrupted. First, we investigated the effects of reducing insulin gene dosage on glucose homeostasis and body mass in leptin deficient ob/ob mice. Next we explored the significance of leptin signalling in pancreatic β cells. To determine whether the glucoregulatory actions of leptin are conserved across rodent species, we explored the effects of leptin deficiency in rats, and used this model to investigate the hierarchy of metabolic defects that arise as a result of impaired leptin action. Finally, we describe a novel mouse model to selectively knock out leptin in a temporal and tissue-specific manner. Conclusions: We show that reduction of circulating insulin levels prevents obesity, but results in hyperglycemia in ob/ob mice. Furthermore, we show that direct leptin signalling in β cells is insufficient to restore euglycemia. In addition, we demonstrate that leptin deficiency produces a similar metabolic phenotype in rats as in mice. Finally, we suggest that loss of insulin sensitivity may be a primary metabolic defect that results from leptin deficiency in rats. Together, these results provide further insight into the glucoregulatory mechanisms of leptin that may be used to develop therapeutic strategies to treat obesity and diabetes.

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2017-08-16

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/62657

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/