Date of Award
Doctor of Philosophy (PhD)
Leptin is an adipocyte-derived hormone that regulates energy balance, metabolism, and the neuroendocrine response to altered nutrition. Mice lacking leptin (ob/ob) or its receptor (db/db) are massively obese and hyperphagic. They also have increased triglyceride deposits in multiple peripheral organs, including the liver, massively enlarged and steatotic. Leptin elicits a metabolic response that cannot be explained by its anorectic effects alone. This response is characterized by weight loss, depletion of lipid from peripheral tissues, and enhanced insulin sensitivity. The mechanisms underlying these actions were largely unknown. This thesis addressed leptin's metabolic effects on the liver, an organ with a critical role in lipid metabolism and glucose homeostasis. The relative contribution of central vs. peripheral leptin action on body weight, neuroendocrine function, and lipid metabolism had not been tested genetically. To address this question, mice with either neuronal (ObRSynIKO) or hepatocyte-specific (ObRAlbKO) deletion of the leptin receptor were studied. ObRSynIKO mice were massively obese and had neuroendocrine abnormalities resembling those of db/db mice, whereas ObRAlbKO mice displayed normal body weight. ObRAlbKO mice had normal liver triglyceride levels, while ObRSynIKO mice had enlarged fatty livers, indicating the liver abnormalities of ob/ob and db/db mice are secondary to defective leptin action the brain. Microarrays were used to explore the basis for leptin's unique effects on the liver. Genes with altered expression in ob/ob liver were identified, and gene expression was profiled following a time course of weight loss induced by either leptin treatment or 1 restriction. Cluster analysis demonstrated a unique transcriptional response to leptin, distinct from pair-feeding. Based on these findings, an algorithm was developed to identify and rank leptin-regulated genes for further functional analysis. The two most strongly leptin-regulated genes were stearoyl-CoA desaturase-1 (SCD-1) and insulin-like growth factor binding protein-2 (IGFBP-2). SCD-1 was specifically repressed during leptin-mediated weight loss, and mice lacking SCD-1 showed markedly reduced adiposity on both a lean (abJ/abJ) and ob/ob background (abJ/abJ; ob/ob), despite higher food intake. abJ/abJ; ob/ob mice also showed a complete correction of the hypometabolic phenotype and hepatic steatosis of ob/ob mice, suggesting that fatty acid oxidation enhanced in the absence of SCD-1. Furthermore, both alcoholic and nonalcoholic fatty liver disease secondary to lipodystrophy were markedly attenuated in SCD-1 deficient mice. IGFBP-2 was specifically induced during leptin treatment. Double mutant IGFBP- 2~/~;ob/ob mice were partially resistant to leptin, suggesting that IGFBP-2 induction be necessary for the full spectrum of leptin's metabolic effects. Thus, central leptin action coordinates a specific transcriptional response in the liver, which mediates the metabolic effects of leptin. SCD-1 and IGFBP-2 both have a role in leptin-mediated weight loss. Further study of these and other leptin-regulated genes may further elucidate the molecular basis for leptin's unique effects on metabolism.
Cohen, Paul, "Leptin and the Control of Body Weight and Metabolism: Role for Stearoyl CoA Desaturase-1 and Other Leptin-Regulated Genes in the Liver" (2002). Student Theses and Dissertations. 348.