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Glucoregulatory actions of leptin in rodent models of diabetes

University of British Columbia

The hormone leptin reduces food intake and increases energy expenditure; leptin deficient rodents and humans are severely obese with impaired glucose homeostasis, and leptin therapy reverses these metabolic abnormalities. Based on this, leptin gained significant interest as a potential therapeutic agent to combat obesity; however, it was soon discovered that most obese humans are resistant to its anorectic actions and the initial excitement over the therapeutic applicability of leptin dwindled. It is now evident that leptin regulates glucose metabolism independent of its actions on body weight. Underlining this, leptin displays the remarkable ability to reverse hyperglycemia in rodent models of type 1 diabetes. These findings sparked interest in leptin as a therapy for type 1 diabetes. The overarching goal of this thesis was to perform pre-clinical studies to elucidate the mechanism by which leptin lowers blood glucose levels in insulin deficient mice and assess whether resistance to these effects of leptin can occur. To this end, we assessed the plasma metabolomic profile of leptin-treated insulin deficient mice, which revealed global alterations in amino acid metabolism. Thus, we characterized amino acid utilization in leptin-treated mice, tested the mechanistic role of amino acid catabolism genes, and extensively characterized the metabolic changes in the liver using an 'omics' based approach. In addition, we assessed whether recapitulating leptin-mediated changes in the liver using a small molecule can mimic the glucose lowering actions of leptin. Lastly, we assessed whether hyperleptinemia or high-fat intake, which are reported to cause resistance to the weight reducing actions of leptin, also impede glucose lowering effects of leptin. This thesis revealed that leptin globally alters the liver metabolic profile to suppress the utilization of amino acids for glucose production and recapitulating the transcriptomic profile of leptin therapy with a novel small molecule can lower blood glucose levels in insulin deficient mice. Furthermore, dietary fats, but not hyperleptinemia, causes resistance to the glucose lowering actions of leptin in insulin deficient mice. Collectively, these investigations help elucidate the mechanism by which leptin reverses hyperglycemia in insulin deficient mice and shed insight into the suitability of leptin as a therapy for diabetes.

Text

2019-08-26

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71431

Cell and Developmental Biology

University of British Columbia

UBCV

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