Genomics 2 !!

Diet effects on weight gain and body composition in high growth (hg/hg) mice


A LARGE NUMBER OF GROWTH DISORDERS in humans have been classified as overgrowth syndromes . Many of these syndromes have genetic origins and may lead to hormonal imbalances that affect growth patterns under different nutritional environments. A typical example is the effect of an increased energy intake leading to obesity in children, as well as an increase in height relative to leaner children . The underlying mechanisms of nutrition and linear growth are central to understanding the etiology of many of the interactions leading to overgrowth.

The genetics of growth has extensively used the laboratory mouse as a model of study. However, the majority of mouse mutations affecting growth result in a reduction in body size . Increased size mutants have largely been those associated with obesity . More recently, some mouse knockouts with increased size have been described, but they have specific tissue abnormalities or endocrine dysfunction. In contrast to these models, one natural mutation in the mouse, high growth (hg) , has a generalized increase in body size and is not obese . Therefore, it constitutes a valuable model with which to study genetic and nutritional aspects of overgrowth.
The hg locus is a partially recessive mutation that dramatically enhances postweaning weight gain and adult body size. Genetic analysis of the mutation has determined that the hg locus is a 500-kb deletion in mouse chromosome 10 . The identification and characterization of genes within the hg deletion are in progress, and a positional candidate gene has been identified . However, the causality of this particular phenotype is not yet fully understood. Mice homozygous for the deletion show an increased growth rate of up to 50% accompanied by a higher energetic efficiency and/or lower maintenance requirements . The effects of the mutation are detected early in development, manifested by delayed muscular cell fusion and an increase in muscle fiber number . Interestingly, high growth mice have lower concentrations of growth hormone (GH) but much higher concentrations of insulin-like growth factor I (IGF-I) in plasma than do normal mice . Despite substantial changes in growth rate and size, the mice are proportional in the size of body components .

Nutrition is the most important nongenetic factor affecting growth and body composition traits in mammals . Moreover, complex interactions between genotype and diet composition have been detected in experiments evaluating growth in mice . Therefore, the goal of this study was to assess the importance of genotype x diet interactions on the effects of a major locus regulating animal growth. High growth and control mice were fed diets varying in protein and energy content from 3 to 12 wk of age. To describe the effects of hg on important physiological processes related to growth, we measured weight gain, feed intake, body composition and the concentrations of insulin, leptin, IGF-I, and glucose.

Genomics !!

Cholesteryl ester hydrolase in human monocyte/macrophage: cloning, sequencing, and expression of full-length cDNA



THE FORMATION of macrophage-derived foam cells is a central event in the development of fatty streaks within the arterial wall and progression of atherosclerosis. The unregulated uptake of modified lipoproteins by macrophages via scavenger-receptors leads to the deposition of cholesterol esters and the formation of foam cells. Stored cholesterol esters, present as cytoplasmic droplets, exist in dynamic equilibrium with unesterified cholesterol undergoing continuous hydrolysis and reesterification in a process known as the "cholesterol ester cycle." Neutral cholesteryl ester hydrolase (CEH) catalyzes the hydrolytic reaction, whereas reesterification is catalyzed by acyl-CoA cholesterol acyltransferase (ACAT). Free cholesterol released by CEH moves to the plasma membrane and is subsequently transferred to a cholesterol acceptor [e.g., high-density lipoprotein (HDL)], resulting in net cellular cholesterol efflux. Macrophages with high neutral CEH activity accumulate less cholesterol esters in the presence of atherogenic ß-migrating very low-density lipoproteins (ß-VLDL) in comparison to macrophages with low CEH activity . Animal models of atherosclerosis, such as the hypercholesterolemic rabbit and the White Carneau pigeon, appear to possess macrophages in which stored cholesterol esters are resistant to hydrolysis and subsequent mobilization . Hence, CEH activity may be a limiting factor in the mobilization of cholesterol esters from foam cells and therefore may play a role in determining the susceptibility to atherosclerosis.

Despite the obvious significance of cholesterol ester hydrolytic enzymes in atherogenesis, the identity of CEH in macrophages remains obscure. Several lines of evidence suggest that the enzyme responsible for cholesterol ester hydrolysis in murine macrophages is similar to hormone-sensitive lipase (HSL) present in adipose and steroidogenic tissues . Although Reue et al. detected HSL mRNA in the human monocyte cell line THP-1, Contreras et al. failed to detect HSL mRNA in human macrophages. Li and Hui recently reported the absence of HSL in human macrophages and demonstrated the expression of bile salt-stimulated CEH, similar to secretory pancreatic CEH. Since this enzyme was secreted from the cells, Li and Hui proposed that it was unlikely to play a role in the intracellular cholesterol metabolism and suggested that another CEH may be responsible for cholesteryl ester metabolism in human macrophages.