TY - JOUR
T1 - Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance
AU - Langhi, Cédric
AU - Arias, Noemí
AU - Rajamoorthi, Ananthi
AU - Basta, Jeannine
AU - Lee, Richard G.
AU - Baldán, And Ángel
N1 - Publisher Copyright:
© 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/1
Y1 - 2017/1
N2 - 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 (leptindeficient 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.-Langhi, C., N. Arias, A. Rajamoorthi, J. Basta, R. G. Lee, and Á. Baldán. Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance.
AB - 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 (leptindeficient 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.-Langhi, C., N. Arias, A. Rajamoorthi, J. Basta, R. G. Lee, and Á. Baldán. Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance.
KW - Antisense therapy
KW - Diabetes
KW - Fatty liver
KW - Steatosis
KW - Supplementary cell death-inducing dffa-like effector C
UR - http://www.scopus.com/inward/record.url?scp=85009909723&partnerID=8YFLogxK
U2 - 10.1194/jlr.M069799
DO - 10.1194/jlr.M069799
M3 - Article
C2 - 27884961
AN - SCOPUS:85009909723
SN - 0022-2275
VL - 58
SP - 81
EP - 91
JO - Journal of lipid research
JF - Journal of lipid research
IS - 1
ER -