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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

Authors :
Mohammad A. Hossain
Dominic S. Ng
Stephanie A. Schroer
Lixin Li
Philip W. Connelly
Minna Woo
Lu Liu
Sabreena Sadat
Lu Huogen
Lauren Hager
Laetitia Tam
I. George Fantus
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.

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