title: Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance.
abstract: Obesity is a component of the metabolic syndrome, mechanistically linked to diabetes, fatty liver disease, and cardiovascular disease. Proteins that regulate the metabolic fate of intracellular lipid droplets are potential therapeutic candidates to treat obesity and its related consequences. CIDEC (cell death-inducing DFFA-like effector C), also known in mice as Fsp27 (fat-specific protein 27), is a lipid droplet-associated protein that prevents lipid mobilization and promotes intracellular lipid storage. The consequences of complete loss of FSP27 on hepatic metabolism and on insulin resistance are controversial, as both healthy and deleterious lipodystrophic phenotypes have been reported in Fsp27-/-mice. To test whether therapeutic silencing of Fsp27 might be useful to improve obesity, fatty liver, and glycemic control, we used antisense oligonucleotides (ASOs) in both nutritional (high-fat diet) and genetic (leptin-deficient ob/ob) mouse models of obesity, hyperglycemia, and hepatosteatosis. We show that partial silencing Fsp27 in either model results in the robust decrease in visceral fat, improved insulin sensitivity and whole-body glycemic control, and tissue-specific changes in transcripts controlling lipid oxidation and synthesis. These data suggest that partial reduction of FSP27 activity (e.g., using ASOs) might be exploited therapeutically in insulin-resistant obese or overweight patients.
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology Saint Louis University, Saint Louis, MO 63104.
authors.forename: Cédric
authors.initials: C
authors.lastname: Langhi
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology Saint Louis University, Saint Louis, MO 63104.
authors.forename: Noemí
authors.initials: N
authors.lastname: Arias
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology Saint Louis University, Saint Louis, MO 63104.
authors.forename: Ananthi
authors.initials: A
authors.lastname: Rajamoorthi
authors.affiliation: Department of Internal Medicine, Saint Louis University, Saint Louis, MO 63104.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Basta
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA 92010.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Edward A. Doisy Department of Biochemistry & Molecular Biology Saint Louis University, Saint Louis, MO 63104 abaldan1@slu.edu.|Center for Cardiovascular Research Saint Louis University, Saint Louis, MO 63104.|Liver Center, Saint Louis University, Saint Louis, MO 63104.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Baldán
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D066292:Lipid Droplets / Q000378:metabolism / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D016376:Oligonucleotides, Antisense; D011506:Proteins; C525805:fat-specific protein 27, mouse
keywords: antisense therapy; cell death-inducing DFFA-like effector C; diabetes; fatty liver; steatosis