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 dietinduced 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-AMPK␣, PGC1␣, 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. LCAT2 is an important enzyme in the regulation of high density lipoprotein (HDL) metabolism and in modulating plasma HDL cholesterol levels. LCAT mediates the esterification of cholesterol primarily in HDL but also to a limited extent in LDLs. Familial complete LCAT deficiency in humans is characterized by extremely low levels of plasma HDL cholesterol. In addition, commonly observed lipid phenotypes include elevated plasma level of phospholipid, free cholesterol to cholesterol ester ratio, and modest hypertriglyceridemia, the latter characterized by combined hepatic triglyceride overproduction and partially reduced lipoprotein lipase activity (1, 2). Recent human studies in a large cohort of subjects with familial LCAT deficiencies suggest that low LCAT may protect against atherosclerosis (3). However, studies in subjects with low LCAT in the general population yielded conflicting results (4). On the other hand, the potential role for LCAT in the modulation of glucose and energy homeostasis has received little attention. Our laboratory was the first to report that, in the LDL receptor knock-out mouse background and under chow-fed conditions, the genetic absence of LCAT (Ldlr Ϫ/Ϫ ϫLcat Ϫ/Ϫ mice) is associated with enhanced insulin sensitivity when compared with the Ldlr

Background: Hepatic ER stress promotes insulin resistance, but the role of cholesterol in this pathway is unknown. Results: LCAT-deficient mice maintain a low ER cholesterol and are protected from cholesterol-induced ER stress. Conclusion: ER cholesterol, not tissue cholesterol, is crucial for hepatic ER stress development. Significance: Modulators of hepatic ER cholesterol may be novel targets to treat diabetes.

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