First-generation (1-) male and female rat pups were either reared artificially on a high-carbohydrate (HC) or a high-fat (HF) formula or nursed by mother (MF) from day 4 and weaned onto a stock diet on day 24. 1-HC rats compared with sex-matched control rats (1-HF and 1-MF) were hyperinsulinemic and mildly obese by day 60. We investigated the effect of maternal hyperinsulinemia on the second generation (2-) by intragroup breeding. The 2-HC male and female rats were hyperinsulinemic on day 45, had significantly increased growth rate from approximately day 60 onward, and became obese as evidenced by increased adipose tissue mass due to hypertrophy on day 100. The lipogenic capacity of liver and adipose tissues was significantly higher in the 2-HC than in control rats. Thus the metabolic changes that occurred in the first-generation rats fed a HC formula during early postnatal life not only persisted into their adult life but were also passed on to the next generation.

We have investigated pancreatic changes associated with hyperinsulinemia and an insulin secretory response to an oral glucose load in a new rat model for obesity. Male Sprague-Dawley pups were reared on a high-carbohydrate (HC) or high-fat (HF) formula by gastrostomy during the suckling period and were weaned onto a stock diet. These animals remained either nutritionally unchallenged or challenged with a high-sucrose diet during the postweaning period. The HC formula-fed animals showed increased insulin concentrations in the plasma and pancreas and also showed impaired insulin secretory response compared with mother-fed control or HF animals in adult life. Immunocytochemical and morphometric studies revealed that hyperinsulinemia in the HC animals during the preweaning period and also in adult life was associated with hypertrophy of beta-cells in the pancreas. The results show that consumption of a HC formula during the suckling period influences pancreatic islet morphology resulting in hyperinsulinemia which eventually leads to the development of obesity later in adult life.

Results: AA diabetic women, like WA diabetic women, had a larger average very low density lipoprotein (VLDL) size, elevated levels of small low density lipoprotein cholesterol (LDL-C), and lower levels of small high density lipoprotein cholesterol (HDL-C), when compared to lean controls (p Ͻ 0.05). These differences were accompanied by higher VLDL-triglycerides (TG) and LDL-C in WA (p Ͻ 0.05), but not in AA. Although the effects of obesity and diabetes on lipoprotein subpopulation were fairly similar for AA and WA, some racial differences, particularly with respect to HDL, were observed. Discussion:The atherogenic perturbations in lipoprotein profiles of obese AA women, particularly those with diabetes, were relatively similar to those found in WA women and may be contributing to the increased rate of cardiovascular disease (CVD) in AA with obesity and diabetes. The parameters of subpopulation distribution may provide better markers for CVD than lipid concentrations alone, particularly in AA women. Furthermore, subtle racial differences in lipoprotein profiles suggest that race-specific criteria may be needed to screen patients for CVD.

Considerable evidence suggests that there are ethnic differences in lipid metabolism between African American and Caucasian women, which may result in increased synthesis of fat in adipose tissue. The purpose of this study was to measure the in vitro rates of [14C]glucose incorporation into the glyceride-glycerol backbone of triglycerides (TG) and diglycerides (DG) in abdominal subcutaneous (SAT) and omental adipose tissue (OAT). Morbidly obese [African American (n = 15): body mass index (BMI) = 45 +/- 2.3; Caucasian (n = 18): BMI = 51 +/- 2.3] and preobese [African American (n = 7): BMI = 27 +/- 1.0; Caucasian (n = 7): BMI = 25 +/- 1.0] women were examined in this study. There were no significant differences in the rates of synthesis of either TG or DG in SAT of either preobese or obese women. On the other hand, both preobese and obese African American women had higher rates of synthesis of TG in OAT compared with their Caucasian counterparts. This increase in TG synthesis in OAT was not due to differences in cell size or rates of reesterification. Thus African American woman have an increased capacity to synthesize TG in OAT compared with Caucasian women, which may contribute to the higher prevalence of obesity in African American women.

Objective-Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. Methods and Results-Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098Ϯ7486 m 2 . No lesions greater than 1000 m 2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. Key Words: cholesterol Ⅲ FPLC Ⅲ VLDL Ⅲ LDL Ⅲ HDL obesity C holesteryl ester transfer protein (CETP) is a glycoprotein that catalyzes the transfer of neutral lipids between the plasma lipoproteins. In this respect, this enzyme is involved in at least one arm of reverse cholesterol transport (RCT), an antiatherogenic process by which cholesterol is cleared from peripheral tissues. 1 Even so, the atherogenic nature of CETP has been the subject of much debate because both increased and decreased CETP expression have been linked to elevated risk and incidence of vascular disease. 2 Thus, the atherogenic nature of CETP is thought to depend on the metabolic context in which it influences lipoprotein metabolism. Conclusions-TheObesity is a metabolic condition afflicting more than one third of the population of the United States. 3 Obesity is accompanied by both a mild increase in vascular disease complications 4 as well as elevated plasma CETP activity. [5][6][7][8][9] It is unclear whether this perturbation in CETP activity contributes to altered lipoprotein profiles and elevated vascular disease risk or is a normal consequence of elevated cholesterol levels observed in these patients. 5,10 Interestingly, obese patients with type 2 diabetes have a higher risk of vascular disease complications, 11 higher circulating cholesterol levels, 5,10 and depressed levels of plasma CETP concentrations 5,12 compared with obese nondiabetic controls. This suppressive effect of diabetes on plasma CETP is not apparent in nonobese individuals. [13][14][15][16] We have hypothesized that depressed plasma CETP levels in obese patients with diabetes may hinder the clearance of the high levels of peripheral cholesterol that accompany obesity and contribute to elevated atherosclerosis in these patients.The purpose of this study was to examine the effects of overexpressing CETP...

Cholesteryl ester transfer protein (CETP) is a plasma enzyme that can modulate the profile of lipoproteins and is thus considered: 1) a mediator of vascular disease; and 2) a therapeutic target for vascular disease. In the present study, we pursued a better understanding of the effect of type 2 diabetes on the expression of CETP in obese patients. Obesity was accompanied by a 20% elevation in plasma CETP that was eliminated with the development of diabetes. These differences were observed for both men and women and were due to variations in the amount of CETP protein in the plasma. The mRNA and protein of both the full-length (CETPFL) and alternatively spliced (CETPDelta9) forms of CETP were lower in the liver, but not in either sc or omental adipose tissue depots, of diabetic obese subjects. Sterol response element binding proteins 1 and 2 were also lower in liver homogenates, suggesting that these transcription factors may mediate the effects of type 2 diabetes on hepatic CETP expression. Thus, the suppressive effects of type 2 diabetes in obese subjects are observed in both men and women and may be due, at least in part, to a suppression of hepatic CETP expression.

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Neonatal rat pups were artificially reared on isocaloric diets high in carbohydrate (HC) or high in fat (HF) or were naturally reared on mother's milk (MF). The HC adult rats were hyperinsulinemic, normoglycemic, and obese. This study investigates pancreatic islet insulin release (IR) of the adult first-generation (1-) diet-regulated animals and their second-generation (2-) progeny. Male rat 1-HC islets had higher basal IR than either 1-MF or 1-HF control groups. In addition, glucose (17 mM) failed to increase IR above basal values in 1-HC islets, whereas it stimulated IR in 1-MF and 1-HF islets. Similar secretory responses were evoked by 2-ketoisocaproic acid (2-KIC). Female rat 1-MF and 1-HF islets also had higher glucose-stimulated IR compared with 1-HC islets. Male rat 2-HC islets had higher basal IR and reduced sensitivity to glucose and 2-KIC compared with 2-MF islets, which coincided with hyperinsulinemia. Glyceraldehyde-3-phosphate dehydrogenase activity in 1-HC and 2-HC islets was higher than in MF islets. These data suggest that basal IR is higher in islets isolated from animals reared as neonates on a diet high in carbohydrate. Alterations in beta-cell metabolism and secretion probably contribute to the hyperinsulinemia, reduced glucose sensitivity, and glucose intolerance characteristic of this rat model.