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Lecithin Cholesterol Acyltransferase Null Mice Are Protected from Diet-induced Obesity and Insulin Resistance in a Gender-specific Manner through Multiple Pathways
- Source :
- Journal of Biological Chemistry. 286:17809-17820
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Complete lecithin cholesterol acyltransferase (LCAT) deficiency uniformly results in a profound HDL deficiency. We recently reported unexpected enhanced insulin sensitivity in LCAT knock-out mice in the LDL receptor knock-out background (Ldlr(-/-)×Lcat(-/-); double knock-out (DKO)), when compared with their Ldlr(-/-)×Lcat(+/+) (single knock-out (SKO)) controls. Here, we report that LCAT-deficient mice (DKO and Lcat(-/-)) are protected against high fat high sucrose (HFHS) diet-induced obesity without hypophagia in a gender-specific manner compared with their respective (SKO and WT) controls. The metabolic phenotypes are more pronounced in the females. Changes in endoplasmic reticulum stress were examined as a possible mechanism for the metabolic protection. The female DKO mice developed attenuated HFHS-induced endoplasmic reticulum stress as evidenced by a lack of increase in mRNA levels of the hepatic unfolded protein response (UPR) markers Grp78 and CHOP compared with SKO controls. The DKO female mice were also protected against diet-induced insulin resistance. In white adipose tissue of chow-fed DKO mice, we also observed a reduction in UPR, gene markers for adipogenesis, and markers for activation of Wnt signaling. In skeletal muscles of female DKO mice, we observed an unexpected increase in UCP1 in association with increase in phospho-AMPKα, PGC1α, and UCP3 expressions. This increase in UCP1 was associated with ectopic islands of brown adipocytes between skeletal muscle fibers. Our findings suggest that LCAT deficiency confers gender-specific protection against diet-induced obesity and insulin resistance at least in part through regulation in UPR, white adipose tissue adipogenesis, and brown adipocyte partitioning.
- Subjects :
- Male
Sucrose
medicine.medical_specialty
Adipose Tissue, White
Adipose tissue
White adipose tissue
AMP-Activated Protein Kinases
Biology
Biochemistry
Ion Channels
Mitochondrial Proteins
Phosphatidylcholine-Sterol O-Acyltransferase
Mice
Insulin resistance
Lecithin Cholesterol Acyltransferase Deficiency
Internal medicine
Brown adipose tissue
medicine
Animals
Uncoupling Protein 3
Obesity
Muscle, Skeletal
Endoplasmic Reticulum Chaperone BiP
Molecular Biology
Heat-Shock Proteins
Uncoupling Protein 1
Mice, Knockout
Sex Characteristics
Lecithin cholesterol acyltransferase deficiency
Cell Biology
medicine.disease
Dietary Fats
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Thermogenin
Diet
Wnt Proteins
Metabolism
medicine.anatomical_structure
Endocrinology
Receptors, LDL
Adipogenesis
Sweetening Agents
LDL receptor
Trans-Activators
Unfolded Protein Response
Female
Insulin Resistance
Transcription Factor CHOP
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 286
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....c33e1e281b52580d11b527ead741d6ba
- Full Text :
- https://doi.org/10.1074/jbc.m110.180893