James R. Levy

Dietary n‐3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil–fed animals weighed less and had less body fat. In fish oil–fed animals, liver triglyceride was lower by 27% (P < .05) and 73% (P < .01) than in control‐ and lard‐fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARα, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1‐c, FAS, SCD‐1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n‐3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis. (HEPATOLOGY 2004;39:608–616.)

Total Parenteral Nutrition Increases Serum Leptin Concentration in Hospitalized, Undernourished Patients

BACKGROUND The hormone leptin has putative roles in both body weight homeostasis (chronic) and satiety (acute). To determine if this dual regulation is observed in hospitalized, undernourished patients, serum leptin concentration was measured before and during total parenteral nutrition (TPN) infusion. METHODS Six consecutive patients were considered undernourished, as assessed by an independent multidisciplinary nutrition team, and TPN was prescribed at an initial rate of between 5023.2 and 7333.2 kJ in the first 24 hours. Serum leptin, insulin, and glucose were measured before the infusion and at 3 and 22 hours after initiation of TPN. RESULTS Baseline serum leptin concentrations correlated well with the patients body mass index (BMI; r2 = .85, p<.05). Three hours of TPN infusion produced only modest changes in circulating leptin. However, after 22 hours, leptin concentrations increased by 1.8+/-0.5-fold (p<.05), and this increase was independent of any change in body weight. CONCLUSIONS Basal leptin concentrations correlate well with BMI. TPN induces a rise in leptin concentration independent of body weight. Leptin secretion is dually regulated in hospitalized, undernourished patients.

Effect of Bile Acid Composition and Manipulation of Enterohepatic Circulation on Leptin Gene Regulation

In the rat, the ob gene product, leptin, putatively regulates energy balance via appetite control and energy expenditure. Bile acids in the intestinal lumen are necessary for efficient absorption of dietary lipids and may trigger the release of regulatory peptides. To investigate whether bile acids play a role in leptin gene expression, we altered the bile acid pool and then measured leptin mRNA levels in adipose tissue. Rats fed cholic acid (1% of chow wt/wt) for 2 weeks did not gain weight as rapidly as pair-fed control animals. Despite the lower weight, normalized leptin mRNA levels were 24% greater in cholic acid-fed rats compared with controls. Conversely, cholestyramine, a bile acid sequestrant, in chow (5% wt/wt) resulted in a 26% decline in leptin mRNA. Ligation of the common bile duct or chronic biliary diversion, experimental manipulations that decreased the intestinal concentration of bile salts, decreased leptin gene expression by 30% and 50%, respectively. A fluid and electrolyte (F/E) solution with and without taurocholate (36 micromol/h x 100 g rat[-1]) was then infused for 12 hours into the duodenum in animals with chronic biliary diversion. Taurocholate infusion resulted in a fourfold increase in steady-state adipocyte leptin mRNA levels compared with F/E infusion. Intravenous infusion of taurocholate or incubation of cultured adipocytes with taurocholate had no effect on leptin mRNA levels. We conclude that bile acids upregulate leptin gene expression indirectly, probably via effects on the absorption of dietary lipids or the release of neurohumoral mediators.

Posttraumatic Stress Disorder and Body Mass Index in Military Veterans: The Richmond Experience

ABSTRACT Military veterans suffering from Posttraumatic Stress Disorder (PTSD) often have comorbid conditions including obesity. They may become disabled either from these comorbid conditions or from PTSD (or from both). Service-connected disability (SCD) is a concept employed by both the Department of Defense and the Department of Veterans Affairs to identify and compensate military veterans with such disabilities. SCD could serve as a measure of the functional impact of PTSD and comorbid obesity and other medical conditions. We reviewed the database of the recently constituted PTSD program at Hunter Holmes McGuire Veterans Affairs Medical Center in Richmond, Virginia. Variables assessed included 1) age, 2) decade of life, 3) height, 4) weight, 5) sex, 6) race, 7) employment status, 8) presence or absence of comorbid psychiatric conditions, 9) presence or absence of comorbid medical conditions, and 10) degree of disability. From the height and weight measurements, we calculated body mass index (BMI). We used SCD to estimate degree of disability in terms of total disability (total SCD) and disability ascribed to PTSD (PTSD-SCD). Results indicated that the mean BMI of the study population was 30.3±5.7 kg/m2. This value was consistent with the current definition of obesity. 83.8% of our study population was either overweight or obese. This rate exceeded the US general population level of 64.5%. SCD and comorbid medical conditions had statistically significant relationships with obesity. Race was almost a statistically significant predictor of obesity. Decade of life, employment status and presence/absence of comorbid psychiatric condition did not separate the obese veteran from the non-obese veteran. Analysis of variance (ANOVA) revealed statistical significant differences in BMI (df = 4, F = 2.921, p = 0.022)among various levels of SCD suggesting a threshold effect. PTSD-related SCD, however, did not have a significant relationship with BMI. The prevalence of overweight and obesity among our sample of veterans with PTSD exceeded current U.S. population rates. Comorbid medical conditions may predispose veterans with PTSD to obesity. SCD had a significant relationship with BMI in that there was a threshold effect in which 30% or greater SCD identified veterans with obesity. The cross-sectional nature of the study and the absence of control populations limit the conclusions that may be drawn from our study. Clearly, more definitive studies are needed with much larger study populations.

Down-Regulated Insulin Receptors in HepG2 Cells Have an Altered Intracellular Itinerary

The delivery of insulin and the insulin receptor into an intracellular compartment may be important for eliciting some of the biologic responses of the cell to the hormone. Internalization of insulin-receptor complexes in cells from hyperinsulinemic type II diabetic patients is diminished, suggesting a possible role for this cellular process in insulin resistance. To examine whether hyperinsulinemia contributes to defective insulin-receptor processing in vitro, cultured hepatoma cells (HepG2) were incubated with high concentrations of (500 ng/ml) insulin from 1-3 days. Insulin induced a decrease in the number of total and surface insulin receptors within 24 hours; however, the hormone did not mediate a change in the number of intracellular receptors. The cellular itinerary of control and down-regulated receptors were then compared. Insulin mediated internalization of down-regulated receptors was impaired compared to control receptors; however, the down-regulated receptors that were internalized recycled back to the plasma membrane more efficiently. By covalently labeling the insulin receptor with the photoactive insulin derivative, 125I-NAPA-DP-insulin, it was demonstrated that the rates of receptor degradation of down-regulated and control receptors were similar. These results suggest that incubating HepG2 cells with high concentrations of insulin alters the cellular itinerary of the insulin receptor.