Protection From Obesity in Mice Lacking the VLDL Receptor

Abstract

Abstract-It has previously been reported that mice lacking the VLDL receptor (VLDLRϪ/Ϫ) exhibit normal plasma lipid levels and a modest decrease in adipose tissue mass. In the present study, the effect of VLDLR deficiency on profound weight gain was studied in mice. Obesity was induced either by feeding of a high-fat, high-calorie (HFC) diet or by crossbreeding mice onto the genetically obese ob/ob background. After 17 weeks of HFC feeding, VLDLRϪ/Ϫ mice remained lean, whereas their wild-type littermates (VLDLRϩ/ϩ) became obese. Similarly, the weight gain of ob/ob mice was less profound in the absence of the VLDLR. Moreover, VLDLR deficiency led to increased plasma triglycerides after HFC feeding. The protection from obesity in VLDLRϪ/Ϫ mice involved decreased peripheral uptake of fatty acids, because VLDLRϪ/Ϫ mice exhibited a significant reduction in whole-body free fatty acid uptake, with no clear differences in food intake and fat absorption. These observations were supported by a strong decrease in average adipocyte size in VLDLRϪ/Ϫ mice of both obesity models, implying reduced adipocyte triglyceride storage in the absence of the VLDLR. These results suggest that the VLDLR plays a role in the delivery of VLDL-derived fatty acids into adipose tissue. The most striking features that distinguish the VLDLR from the LDLR are (1) 8 ligandbinding repeats instead of 7 and (2) its expression pattern among tissues. The VLDLR is highly expressed in skeletal muscle, heart, and adipose tissue and only in trace amounts in the liver, whereas the LDLR is abundantly expressed in the liver. 1,2 A role for the VLDLR in lipoprotein metabolism has been suggested by in vitro experiments showing that the VLDLR binds and internalizes particles that are rich in apolipoprotein (apo) E, such as VLDL, IDL, and chylomicrons. 1,3 The binding of these lipoprotein particles to the VLDLR was stimulated by lipoprotein lipase (LPL) 3,4 and inhibited by a 39-kDa protein named the receptor-associated protein (RAP). 5 In addition to lipoproteins, the VLDLR has been shown to bind several other ligands, including urokinase complexed to its inhibitor, plasminogen activator inhibitor type 1, 6 and thrombospondin-1. 7 Based on its binding characteristics, endothelial localization, 8 and tissue expression pattern, it is hypothesized that the VLDLR facilitates the binding of triglyceride (TG)-rich particles in the capillary bed and subsequent delivery of free fatty acids (FFAs) to tissues active in fatty acid metabolism. 3,9,10 In line with this hypothesis, it was shown in mice that VLDLR mRNA levels are upregulated in heart and downregulated in adipose tissue after prolonged fasting. 11Reciprocally, VLDLR mRNA levels were downregulated in heart and upregulated in adipose tissue of LDLR-deficient mice fed an atherogenic diet. 12 To directly investigate a role for the VLDLR in lipid metabolism, mice were generated lacking the VLDLR by gene targeting. 13 VLDLRϪ/Ϫ mice exhibited no differences in plasma lipoproteins, and the sole abnormality detected was...

Increased Very Low Density Lipoprotein Secretion and Gonadal Fat Mass in Mice Overexpressing Liver DGAT1

“…Mice lacking the VLDLR exhibit normal lipid levels and a modest decrease in epididymal adipose tissue weights and are protected from diet-induced obesity (43,44). These knockout mouse studies and our DGAT study support the hypothesis that an increased plasma VLDL concentration is an important determinant of intra-abdominal obesity, possibly mediated by the VLDLR.…”

Adipose tissue pathways involved in weight loss of cancer cachexia

“…Nevertheless, 105 of these 130 genes were reciprocally regulated by cachexia and obesity. Notably, among the reciprocally regulated genes is the low-density lipoprotein receptor gene, which has been shown to regulate adiposity in experimental models (Goudriaan et al, 2001;Yagyu et al, 2002).…”

Acylation-stimulating Protein (ASP) Deficiency Induces Obesity Resistance and Increased Energy Expenditure in ob/obMice

“…The ob/ob mice have been used to test for protection from obesity in a number of double knockout models, such as the ob/ob VLDL receptor(Ϫ/Ϫ) or the ob/ob PAI-1(Ϫ/Ϫ). In most cases, the decrease in weight, which was evident in the single knockout, was enhanced when examined on the background of the ob/ob obese mouse model (24,25).Leptin is produced by adipocytes (26) and is involved in the regulation of body fat stores. Leptin is critically involved in the regulation of body energy balance via its central actions on food intake and energy expenditure (27).…”

“…The ob/ob mice have been used to test for protection from obesity in a number of double knockout models, such as the ob/ob VLDL receptor(Ϫ/Ϫ) or the ob/ob PAI-1(Ϫ/Ϫ). In most cases, the decrease in weight, which was evident in the single knockout, was enhanced when examined on the background of the ob/ob obese mouse model (24,25).…”