Apolipoprotein E predisposes to obesity and related metabolic dysfunctions in mice

Abstract

Obesity and its related pathologies constitute a major cause of death, with rates increasing at an alarming pace [1]. By the beginning of the millennium, overweight adults accounted for over 15% of the world's population (body mass index > 30, World Health Organization) [2], with this number increasing to 50% within the USA and Europe [3]. Obesity develops as a result of disruption of the homeostasis between food intake and energy expenditure, and therefore factors affecting these processes are the focus of extensive Obesity is a central feature of the metabolic syndrome and is associated with increased risk for insulin resistance and type II diabetes. Here, we investigated the contribution of human apoliprotein E3 and mouse apoliprotein E to the development of diet-induced obesity in response to western-type diet. Our data show that apolipoprotein E contributes to the development of obesity and other related metabolic disorders, and that human apolipoprotein E3 is more potent than mouse apolipoprotein E in promoting obesity in response to western-type diet. Specifically, we found that apolipoprotein E3 knock-in mice fed western-type diet for 24 weeks became obese and developed hyperglycemia, hyperinsulinemia, hyperleptinemia, glucose intolerance and insulin resistance that were more severe than in C57BL/6 mice. In contrast, apolipoprotein E-deficient mice fed westerntype diet for the same period were resistant to diet-induced obesity, had normal plasma glucose, leptin and insulin levels, and exhibited normal responses to glucose tolerance and insulin resistance tests. Furthermore, low-density lipoprotein receptor-deficient mice were more sensitive to the development of diet-induced obesity and insulin resistance than apolipoprotein E-deficient mice, but were still more resistant than C57BL/6 mice, raising the possibility that low-density lipoprotein receptor mediates, at least in part, the effects of apolipoprotein E on obesity. Taken together, our findings suggest that, in addition to other previously identified mechanisms of obesity, apolipoprotein E and possibly the chylomicron pathway are also important contributors to the development of obesity and related metabolic dysfunctions in mice. , LDLrdeficient; LpL, lipoprotein lipase; VLDL, very low-density lipoprotein.

Cholesterol toxicity in pancreatic islets from LDL receptor-deficient mice. Reply to: de Souza JC, de Oliveira CAM, Carneiro EM et al. [letter]

“…Accordingly, we found no difference in glucose tolerance or insulin secretion in Abca1 ;Ldlr -/-mice on a chow diet. This is in agreement with previous literature showing no effect of LDLr deficiency on fasting glucose levels and glucose tolerance in chow-fed mice and slightly improved glucose tolerance in mice fed a Western-type diet [4,5]. At this point the reasons for the discordant results obtained by Bonfleur and colleagues are not clear, as both groups used mice bred on a pure C57Bl6 background at similar ages (16 weeks).…”

Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice

“…In terms of immune response, genetic deletion of LDL receptors has no impact on Ag processing and presentation (37), immunization and Ab production (38), or virus-induced immunopathology (51). The reduced clearance of lipids from the circulation in LDLr 2/2 mice was already evident after 1 wk of the WHF diet and corresponds to the hyperlipidemia reported previously (47,52). However, such acute changes in the circulating lipid levels were not sufficient to substantially alter T cell lipid composition, or responses to an immune challenge, suggesting that elevated levels of circulating lipids alone did not amplify T cell responses.…”

“…This augmented T cell response occurred in the absence of any excess weight gain or IL-6 production, indicating that a diet-induced proinflammatory environment did not cause the altered T cell response. This is because LDLr 2/2 mice gain less weight and fat mass when fed a WHF diet compared with LDLr +/+ mice on the same background and are thus less prone to obesity and obesity-induced inflammation (45)(46)(47). Of interest, an acute dietary intervention of 1 wk did not alter the T cell response in CHS, likely because the lipid composition of T cells had not changed after 1 wk of WHF diet and/or owing to enhanced (polarized) innate inflammatory responses to the acute high-fat feeding (48), at the expense of a lower T cell response.…”

Apolipoprotein A-I Modulates Processes Associated with Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

“…Food intake was assessed by determining the difference in food weight during a 7-d period to ensure reliable measurements, as described previously (26,27).…”

“…At the end of each experiment, at least six mice from each group were sacrificed. Body mass composition was determined as described previously (25,26).…”