title: Deficiency of lipoprotein lipase in neurons modifies the regulation of energy balance and leads to obesity.
abstract: Free fatty acids (FFAs) suppress appetite when injected into the hypothalamus. To examine whether lipoprotein lipase (LPL), a serine hydrolase that releases FFAs from circulating triglyceride (TG)-rich lipoproteins, might contribute to FFA-mediated signaling in the brain, we created neuron-specific LPL-deficient mice. Homozygous mutant (NEXLPL-/-) mice were hyperphagic and became obese by 16 weeks of age. These traits were accompanied by elevations in the hypothalamic orexigenic neuropeptides, AgRP and NPY, and were followed by reductions in metabolic rate. The uptake of TG-rich lipoprotein fatty acids was reduced in the hypothalamus of 3-month-old NEXLPL-/- mice. Moreover, deficiencies in essential fatty acids in the hypothalamus were evident by 3 months, with major deficiencies of long-chain n-3 fatty acids by 12 months. These results indicate that TG-rich lipoproteins are sensed in the brain by an LPL-dependent mechanism and provide lipid signals for the central regulation of body weight and energy balance.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Taussig
authors.forename: Kalyani G
authors.initials: KG
authors.lastname: Bharadwaj
authors.forename: Nicholas V
authors.initials: NV
authors.lastname: DiPatrizio
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002149:Energy Intake; D004734:Energy Metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007031:Hypothalamus / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology*; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D005230:Fatty Acids, Nonesterified; D008074:Lipoproteins; D008071:Lipoprotein Lipase