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OBJECTIVE--Low birth weight is associated with diabetes in adult life. Accelerated or 'catch-up' postnatal growth in response to small birth size is thought to presage disease years later. Whether adult [...]

Estimates of the heritability of obesity in humans range as high as 70% based on twin studies (1). However, obesity in the developed world is increasing too rapidly to be [...], Obesity is one of the most serious threats to human health today. Although there is general agreement that environmental factors such as diet have largely caused the current obesity pandemic, the environmental changes have not affected all individuals equally. To model gene-by-environment interactions in a mouse model system, our group has generated an [F.sub.16] advanced intercross line (AIL) from the SM/J and LG/J inbred strains. Half of our sample was fed a low-fat (15% energy from fat) diet while the other half was fed a high-fat (43% energy from fat) diet. The sample was assayed for a variety of obesity- and diabetes-related phenotypes such as growth rate, response to glucose challenge, organ and fat pad weights, and serum lipids and insulin. An examination in the [F.sub.16] sample of eight adiposity quantitative trait loci previously identified in an [F.sub.2] intercross of SM/J and LG/J mouse strains reveals locus-by-diet interactions for all previously mapped loci. Adip7, located on proximal chromosome 13, demonstrated the most interactions and therefore was selected for fine mapping with microsatellite markers. Three phenotypic traits, liver weight in male animals, serum insulin in male animals, and reproductive fat pad weight, show locus-by-diet interactions in the 127-kb region between markers D13Mitl and D13Mit302. The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains.

The prevalence of obesity and its correlates, such as type 2 diabetes, has increased greatly over the last 20 years (1). There has also been a concomitant change in the [...], Genetic variation in response to high-fat diets is important in understanding the recent secular trends that have led to increases in obesity and type 2 diabetes. The examination of quantitative trait loci (QTLs) for both obesity- and diabetes-related traits and their responses to a high-fat diet can be effectively addressed in mouse model systems, including LGXSM recombinant inbred (RI) mouse strains. A wide range of obesity- and diabetes-related traits were measured in animals from 16 RI strains with 8 animals of each sex fed a high- or low-fat diet from each strain. Marker associations were measured at 506 microsatellite markers spread throughout the mouse genome using a nested ANOVA. Locations with significant effects on the traits themselves and/or trait dietary responses were identified after correction for multiple comparisons by limiting the false detection rate. Nonsyntenic associations of marker genotypes were common at QTL locations so that the significant results were limited to loci still significant in multiple QTL models. We discovered 91 QTLs at 39 locations. Many of these locations (n = 31) also showed genetic effects on dietary response, typically because the loci produced significantly larger effects on the high-fat diet. Fat depot weights, leptin levels, and body weight at necropsy tended to map to the same locations and were responsible for a majority of the dietary response QTLs. Basal glucose levels and the response to glucose challenge mapped together in locations distinct from those affecting obesity. These QTL locations form a panel for further research and fine mapping of loci affecting obesity- and diabetes-related traits and their responses to high-fat feeding.

Obesity is an escalating threat to human health worldwide. Its prevalence has increased throughout the past century so that by 2001, nearly one-fifth of U.S. adults were classified as clinically [...], Obesity and its comorbidities, particularly type 2 diabetes, have become serious public health problems over the past few decades. Although the current pandemic is largely caused by societal environmental changes in diet, variation in response to these changes have, in part, a genetic basis. Here we address the genetic basis for both obesity- and diabetes-related traits themselves and dietary fat responses for these traits in a set of recombinant inbred mouse strains formed from the cross of LG/J with SM/J (LGXSM lines) fed a standard low-fat (15% calories from fat) or high-fat (42% calories from fat) diet. We found substantial genetic variation for most of the traits studied. Weight at time of death, liver weight, and weight of the reproductive fat pad had especially high heritabilities, whereas heart weight and serum levels of free fatty acids and triglycerides had low heritabilities. Genetic correlations were very high among fat pad weights and serum leptin, indicating shared genetic variation between fat levels and hormonal appetite control. These obesity traits were moderately correlated with adult growth, liver weight, and serum insulin and cholesterol levels. A majority of traits also displayed genetic variation in response to a high-fat diet, especially the weight of the reproductive and renal fat pads as well as the liver. Genetic correlations in dietary response followed a pattern similar to that found for the traits themselves. Several strains manifested discordant responses for obesity, glucose, and insulin, consistent with the presence of genotypes protective for diabetes in the presence of obesity. These recombinant inbred strains represent potentially valuable new models for dissecting the complex physiological relationships among obesity and diabetes. Diabetes 53:2700-2708, 2004

Diabetes is a chronic, progressively worsening disease associated with a variety of microvascular and macrovascular complications. Cardiovascular disease (CVD) is the main cause of death in these patients (1,2). During [...]

Most patients with diabetes die from macrovascular complications. Little is known about the pathogenesis of diabetic vascular disease, but recent advances in molecular genetics and oxidation chemistry provide clues to [...]

Lipoprotein lipase (LpL) is an important enzyme that provides tissues with triglyceride-derived fatty acids. LpL activity thus represents a potential mechanism for the delivery of lipid to islet Β cells, [...]

Skeletal muscle is a major site of resting metabolic rate and a target tissue for therapies designed to treat diabetes, dyslipidemia and obesity. Ectopic expression of uncoupling protein-1 (UCP-1) in [...]

PPAR[Alpha] appears to affect both lipid and glucose metabolism. The purpose of this study was to examine the putative role of PPAR[Alpha] on Β-cell function. When fed a high fat, [...]

TNF-[Alpha], a putative mediator of insulin resistance, and LPL, a putative marker of insulin sensitivity, are both expressed in skeletal muscle. Both may influence muscle substrate metabolism and muscle function. [...]