The long-term objective of this application is to uncover mechanisms of body weight regulation through a newly discovered pathway mediated by the enzyme lipoprotein lipase (LPL) in the neuron. LPL is the rate limiting enzyme for the uptake of fatty acids from the hydrolysis of circulating triglyceride-rich lipoproteins for lipid storage and/or oxidation in peripheral tissues. LPL is also present throughout the nervous system including neurons in the hippocampus, hypothalamus, and other brain regions. Mice with neuron-specific deletion of LPL (NEXLPL-/-) are obese on dietary chow by 6 months, and heterozygous mice (NEXLPL) also become obese between 6 and 12 mo. In both NEXLPL-/- and NEXLPL a period of hyperphagia precedes obesity followed by marked reductions in metabolic rate ensue. In both NEXLPL-/- and NEXLPL mice, substantial increases in AgRP mRNA in the hypothalamus occur before the onset of obesity and are less elevated but persist after obesity develops. Preliminary data suggest that the LPL-dependent deficiency and metabolism of specific PUFAs in the hypothalamus leads to this up-regulation of AgRP gene expression.
In Specific Aim #1 well characterized hypothalamic cell lines will be used to test whether LPL deficiency directly leads to increased AgRP gene expression in vitro and whether such regulation depends on the enzyme activity of LPL. Mechanistic studies are designed to pinpoint whether LPL functions in the hypothalamus by regulating fatty acid uptake and whether such regulation also relates to insulin action in these cells.
In Specific Aim #2 mice deficient in LPL only in AgRP-producing neurons will be generated to demonstrate that AgRP-producing neurons in NEXLPL-/- mice are the major site of regulation of energy balance and body weight. Studies to evaluate how dietary fatty acids regulate the phenotype are also planned. Finally, despite the presence of severe obesity at 12 mo, NEXLPL-/- mice have better glucose tolerance than littermate controls, and also demonstrate increases in Mc3r gene expression in the hypothalamus, marked brown adipose tissue (BAT) hyperplasia/hypertrophy and increased BAT UCP-1 gene expression. Experiments in this aim will be directed to determining the mechanism of improved glucose metabolism despite obesity in NEXLPL-/- mice. We believe the clinical relevance of this work relates not only to how dietary lipids carried in lipoproteins control energy balance and body weight, but to mechanisms by which BAT is stimulated and glucose tolerance is preserved. Because obesity is epidemic, more insight into the physiology of body weight regulation including how obesity relates to glucose intolerance is needed. Moreover, from this work novel approaches to the prevention and or treatment of obesity by lifestyle and/or new drugs may be possible. Overall, this is the first observation that TG-rich lipoproteins and their metabolism by LPL in the brain has physiologic relevance, and through a series of experiments we hope to reveal mechanisms of how TG-rich lipoprotein sensing and metabolism in the brain impact energy balance and body weight regulation.

Public Health Relevance

Mice injected with fatty acids directly into the brain have reductions in food intake. We have created a genetically-modified mouse that has an inability to breakdown dietary lipoprotein triglycerides into fatty acids in the brain, and becomes obese. The intent of this proposal is to determine the mechanism by which triglyceride-rich lipoproteins are sensed in the brain and regulate body weight.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Wang, Hong; Wang, Yongping; Taussig, Matthew D et al. (2016) Sex differences in obesity development in pair-fed neuronal lipoprotein lipase deficient mice. Mol Metab 5:1025-32
Yu, Tian; Taussig, Matthew D; DiPatrizio, Nicholas V et al. (2015) Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice. PLoS One 10:e0135113
Libby, Andrew E; Wang, Hong; Mittal, Richa et al. (2015) Lipoprotein lipase is an important modulator of lipid uptake and storage in hypothalamic neurons. Biochem Biophys Res Commun 465:287-92
Pellinen, Jacob; Wang, Hong; Eckel, Robert H (2014) Mice with altered brain lipoprotein metabolism display maladaptive responses to environmental challenges that may predispose to weight gain. Metab Syndr Relat Disord 12:339-46
Wang, Hong; Eckel, Robert H (2014) What are lipoproteins doing in the brain? Trends Endocrinol Metab 25:8-14
Wang, Hong; Eckel, Robert H (2012) Lipoprotein lipase in the brain and nervous system. Annu Rev Nutr 32:147-60
Wang, Hong; Astarita, Giuseppe; Taussig, Matthew D et al. (2011) Deficiency of lipoprotein lipase in neurons modifies the regulation of energy balance and leads to obesity. Cell Metab 13:105-13