title: Lecithin cholesterol acyltransferase null mice are protected from diet-induced obesity and insulin resistance in a gender-specific manner through multiple pathways.
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.
authors: Keenan Research Centre, Li Ka Shing Knowledge Institute, Department of Medicine, St. Michael's Hospital, Toronto M5B 1W8, Canada.
authors: Lixin
authors: L
authors: Li
authors: Mohammad A
authors: MA
authors: Hossain
authors: Sabreena
authors: S
authors: Sadat
authors: Lauren
authors: L
authors: Hager
authors: Lu
authors: L
authors: Liu
authors: Laetitia
authors: L
authors: Tam
authors: Stephanie
authors: S
authors: Schroer
authors: Lu
authors: L
authors: Huogen
authors: I George
authors: IG
authors: Fantus
authors: Philip W
authors: PW
authors: Connelly
authors: Minna
authors: M
authors: Woo
authors: Dominic S
authors: DS
authors: Ng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D013395:Sucrose / Q000008:administration & dosage / Q000009:adverse effects; D013549:Sweetening Agents / Q000008:administration & dosage / Q000009:adverse effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D056811:Unfolded Protein Response / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D004041:Dietary Fats; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007473:Ion Channels; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011973:Receptors, LDL; D013549:Sweetening Agents; D015534:Trans-Activators; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3; D051153:Wnt Proteins; D051742:Transcription Factor CHOP; D013395:Sucrose; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D055372:AMP-Activated Protein Kinases