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.
Highlights
LCAT2 is an important enzyme in the regulation of high density lipoprotein (HDL) metabolism and in modulating plasma
We observed for the first time that lecithin cholesterol acyltransferase (LCAT)-deficient mice develop a gender-specific protection from high fat high sucrose (HFHS) diet-induced obesity and insulin resistance in the absence of hypophagia
Excess caloric intake-induced hypertrophic obesity is linked to activation of a number of the unfolded protein response (UPR) pathways as characterized by up-regulation of mRNA levels of the chaperone Grp78 as well as CHOP, and these changes correlated well with enhanced hepatic levels of phospho-PERK and phospho-eIF2␣
Summary
Animals—C57Bl/6 mice and LdlrϪ/Ϫ mice in C57Bl/6 background were acquired from Jackson Laboratories. Quantitative densitometry of immunoblots was performed, and the relative content of each sample protein was calculated based on the relative optical density value after normalizing by the optical density value of the internal control. Western Blot Analysis of Skeletal Muscle Proteins—After an overnight fast, the mice were sacrificed, and the quadriceps muscles were immediately dissected and snap frozen in liquid N2. Western Blot Analysis of Fat Depot Proteins—After an overnight fast, the mice were sacrificed, and fat tissues from specific depots: interscapular brown adipose tissue (iBAT), subcutaneous white adipose tissue (sWAT), inguinal WAT (ingWAT), and epididymal WAT, were immediately dissected and snap frozen in liquid N2. Glucose Tolerance Test—After an overnight fast, serial plasma glucose levels were determined by glucometer after an intraperitoneal bolus injection of glucose at 1.125 g/kg of body weight as previously described [28]. A two-tailed p value of Ͻ0.05 was considered statistically significant
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