Showing papers by "Jacob Raber published in 2000"
TL;DR: It is shown that Dgat-deficient (Dgat−/−) mice are viable and can still synthesize triglycerides, and these mice are lean and resistant to diet-induced obesity.
Abstract: Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides Moreover, these mice are lean and resistant to diet-induced obesity The obesity resistance involves increased energy expenditure and increased activity Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity
918 citations
TL;DR: Testing the spatial memory of transgenic mice carrying human forms of apolipoprotein E finds that it is impaired in mice with ApoE4 but not those with apoE3, even though the levels of β-amyloid in their brains are comparable.
Abstract: Key proteins implicated in the development of Alzheimer's disease are the β-amyloid precursor protein, which gives rise to the β-amyloid peptides that accumulate in the deteriorating brain1,2, and the different isoforms of apolipoprotein E (apoE). The apoE4 variant increases the risk of developing the disease compared with apoE3 (ref. 3). We have tested the spatial memory of transgenic mice carrying human forms of these proteins and find that it is impaired in mice with apoE4 but not those with apoE3, even though the levels of β-amyloid in their brains are comparable. The fact that apoE3, but not apoE4, can protect against cognitive deficits induced by β-amyloid may explain why human apoE4 carriers are at greater risk of developing Alzheimer's than apoE3 carriers.
210 citations
TL;DR: It is demonstrated that apolipoprotein E (apoE) deficiency results in age-dependent dysregulation of the HPA axis through a mechanism affecting primarily the adrenal gland, which supports a key role for apoE in the tonic inhibition of steroidogenesis and HPAaxis activity.
Abstract: Several neurological diseases are frequently accompanied by dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates the secretion of glucocorticoids (GCs), which play important roles in diverse brain functions, including cognition, emotion, and feeding. Under physiological conditions, GCs are adaptive and beneficial; however, prolonged elevations in GC levels may contribute to neurodegeneration and brain dysfunction. In the current study, we demonstrate that apolipoprotein E (apoE) deficiency results in age-dependent dysregulation of the HPA axis through a mechanism affecting primarily the adrenal gland. Apoe(-/-) mice, which develop neurodegenerative alterations as they age, had an age-dependent increase in basal adrenal corticosterone content and abnormally increased plasma corticosterone levels after restraint stress, whereas their plasma and pituitary adrenocorticotropin levels were either unchanged or lower than those in controls. HPA axis dysregulation was associated with behavioral and metabolic alterations. When anxiety levels were assessed in the elevated plus maze, Apoe(-/-) mice showed more anxiety than wild-type controls. Apoe(-/-) mice also showed reduced activity in the open field. Finally, Apoe(-/-) mice showed age-dependent increases in food and water intake, stomach and body weights, and decreases in brown and white adipose tissues. These results support a key role for apoE in the tonic inhibition of steroidogenesis and HPA axis activity and have important implications for the behavioral analysis of Apoe(-/-) mice.
131 citations