Circadian Expression of Procolipase in the Liver: A Metabolic Signal

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DESCRIPTION (provided by applicant): There is emerging evidence that alterations in circadian rhythms contribute to obesity in humans. Although the molecular mechanisms of the circadian clock are mostly described, the output pathways from the clock to metabolism and behavior are less well understood. The recent description of ectopic procolipase and pancreatic lipase related protein 2 (PLRP2) expression in the liver and other tissues when mice are kept in constant darkness raises the possibility that these proteins contribute to the regulation of feeding behavior and lipid metabolism during environmental stress. Importantly, 5'-AMP, a molecule with a central role in glucose and lipid metabolism, regulated the liver expression of these proteins. Since procolipase is processed post- translationally to release a potent regulator of satiety, enterostatin, and a co-factor for lipolysis, colipase, and PLRP2 is a lipase, these findings have important implications for the circadian regulation of energy homeostasis. Herein, we propose that procolipase and PLRP2 expression in the liver and other peripheral organs represents a novel output that modulates feeding behavior or lipid metabolism in response to environmental triggers. To determine the role of procolipase and PLRP2 in response to environmental signals and to begin unraveling the molecular mechanisms behind procolipase gene expression in the liver, we propose the following Aims: 1) to determine the role of procolipase and PLRP2 in the response to environmental modulators of gene expression by characterizing procolipase-deficient, enterostatin-deficient, PLRP2-deficient and colipase transgene mice; 2) to determine if AMPK-mediated pathways regulate the ectopic expression of procolipase and PLRP2 in response to metabolic stimuli and 3) to identify the cis-acting elements that regulate the ectopic expression of procolipase using HepG2 cells. For Aim 1, we will monitor the body temperature, body weight, activity, feeding behavior and food and water intake of wild-type, procolipase- deficient and enterostatin-deficient mice kept in constant darkness or entrained to restricted-feeding. We will compare the blood and liver levels of triglycerides and fatty acids with the circadian expression of procolipase and PLRP2. The proposed experiments will provide evidence that the ectopic expression of procolipase and PLRP2 has functional consequences. In Aim 2, we test the role of AMP-activated kinase (AMPK) in regulating the ectopic expression of procolipase using HepG2 cells and AMPK-deficient mice. In Aim 3, we will locate the regions of the procolipase gene that contain the cis-elements that mediate the response to AMPK activators. We will perform the promoter analysis in HepG2. These studies will provide the justification for additional studies to identify the responsible transcription factors in a novel pathway from the circadian clock through 5'- AMP to procolipase expression in ectopic tissues. With this knowledge comes the potential to develop novel chronobiological therapies for obesity. PUBLIC HEALTH RELEVANCE: Obesity has become the most common nutritional disorder in the developed world and the co-morbidities of obesity contribute significantly to mortality and medical costs throughout the world. Biological or circadian rhythms have profound effects on energy homeostasis and changes in these rhythms can result in metabolic syndrome or in disordered eating patterns associated with obesity like binge eating or night eating. The proposed studies have the potential to open new avenues in the treatment of obesity through modulating the effects of the environment on biological clocks.