Genetic bases of estrogen-induced pituitary tumorigenesis: identification of genetic loci determining estrogen-induced pituitary growth in reciprocal crosses between the ACI and Copenhagen rat strains.

Estrogens stimulate proliferation and enhance survival of the prolactin (PRL)-producing lactotroph of the anterior pituitary gland and induce development of PRL-producing pituitary tumors in certain inbred rat strains but not others. The goal of this study was to elucidate the genetic bases of estrogen-induced pituitary tumorigenesis in reciprocal intercrosses between the genetically related ACI and Copenhagen (COP) rat strains. Following 12 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), pituitary mass, an accurate surrogate marker of absolute lactotroph number, was increased 10.6-fold in ACI rats and 4.5-fold in COP rats. Composite interval mapping analyses of the phenotypically defined F(2) progeny from the reciprocal crosses identified six quantitative trait loci (QTL) that determine the pituitary growth response to DES. These loci reside on chromosome 6 [Estrogen-induced pituitary tumor (Ept)1], chromosome 3 (Ept2 and Ept6), chromosome 10 (Ept9), and chromosome 1 (Ept10 and Ept13). Together, these six Ept loci and one additional suggestive locus on chromosome 4 account for an estimated 40% of the phenotypic variance exhibited by the combined F(2) population, while 34% of the phenotypic variance was estimated to result from environmental factors. These data indicate that DES-induced pituitary mass behaves as a quantitative trait and provide information that will facilitate identification of genes that determine the tumorigenic response of the pituitary gland to estrogens.

Energy deficit without reducing dietary carbohydrate alters resting carbohydrate oxidation and fatty acid availability.

Reduced carbohydrate (CHO) availability after exercise has a potent influence on the regulation of substrate metabolism, but little is known about the impact of fat availability and/or energy deficit on fuel metabolism when dietary CHO availability is not reduced. The purpose of this study was to determine the influence of a postexercise energy deficit, independent of CHO availability, on plasma substrate concentrations and substrate oxidation. Seven moderately trained men (peak oxygen uptake: 56 +/- 2 ml.kg(-1).min(-1)) performed exhaustive cycling exercise on two separate occasions. The two trials differed only by the meals ingested after exercise: 1) a high-fat diet designed to maintain energy balance or 2) a low-fat diet designed to elicit energy deficit. The CHO and protein contents of the diets were identical. The next morning, we measured plasma substrate and insulin concentrations and CHO oxidation, and we obtained muscle biopsies from the vastus lateralis for measurement of pyruvate dehydrogenase kinase (PDK)-2 and PDK-4 mRNA expression by using RT-PCR. Despite identical blood glucose (5.0 +/- 0.1 and 4.9 +/- 0.1 mM) and insulin (7.9 +/- 1.1 and 8.4 +/- 0.9 microU/ml) concentrations, plasma fatty acid and glycerol concentrations were elevated three- to fourfold during energy deficit compared with energy balance and CHO oxidation was 40% lower (P < 0.01) the morning after energy deficit compared with energy balance (328 +/- 69 and 565 +/- 89 micromol/min). The lower CHO oxidation was accompanied by a 7.3 +/- 2.5-fold increase in PDK-4 mRNA expression after energy deficit (P < 0.05), whereas PDK-2 mRNA was similar between the trials. In conclusion, energy deficit increases fatty acid availability, increases PDK-4 mRNA expression, and suppresses CHO oxidation even when dietary CHO content is not reduced.

Adding fat calories to meals after exercise does not alter glucose tolerance.

A single session of exercise increases insulin sensitivity for hours and even days, and dietary carbohydrate ingested after exercise alters the magnitude and duration of this effect. Although increasing systemic fatty acid availability is associated with insulin resistance, it is uncertain whether increasing dietary fat availability after exercise alters the exercise-induced increase in insulin sensitivity. The purpose of this study was to determine whether adding fat calories to meals after exercise alters glucose tolerance the next day. Seven healthy men cycled 90 min at 66 +/- 2% peak oxygen uptake followed by a maximum of five high-intensity intervals. During the hours after exercise, subjects ingested three meals containing either low-fat (5% energy from fat) or high-fat (45% energy from fat) foods (Low-Fat and High-Fat groups, respectively). Each diet contained the same amount of carbohydrate and protein. An oral glucose tolerance test was performed the next morning. Muscle glycogen and intramuscular triglyceride (IMTG) concentrations were measured in muscle biopsy samples obtained immediately before exercise and the next morning. The day after exercise, muscle glycogen concentration was identical in High-Fat and Low-Fat (393 +/- 70 and 379 +/- 38 mmol/kg dry wt). At the same time, IMTG concentration was approximately 20% greater during High-Fat compared with Low-Fat (42.5 +/- 3.4 and 36.3 +/- 3.3 mmol/kg dry wt; P < 0.05). Despite the addition of approximately 165 g of fat to meals after exercise ( approximately 1,500 kcal) and a resultant elevation in IMTG concentration, glucose tolerance was identical in High-Fat and Low-Fat (composite index: 8.7 +/- 1.0 and 8.4 +/- 1.0). In summary, as long as meals ingested in the hours after exercise contain the same carbohydrate content, the addition of approximately 1500 kcal from fat to these meals did not alter muscle glycogen resynthesis or glucose tolerance the next day.

Postexercise insulin sensitivity is not impaired after an overnight lipid infusion.

High plasma fatty acid availability and a positive energy balance in sedentary individuals reduce insulin sensitivity. This study's purpose was to determine whether high plasma fatty acid availability and systemic caloric excess after exercise also impair insulin sensitivity. On two separate occasions, seven nonobese women performed 90 min of exercise at approximately 65% peak oxygen uptake. In one trial, a lipid + heparin emulsion (Lipid) was infused overnight to increase plasma fatty acid availability. In the other trial, saline was infused as control. The next morning, a muscle biopsy was taken to measure muscle glycogen and intramuscular triglyceride (IMTG) concentrations. Three hours after the overnight infusion was stopped, insulin sensitivity was assessed with an intravenous glucose tolerance test, using minimal model analysis (Si). During the overnight infusions, plasma fatty acid concentration was approximately fourfold higher [means (SD): 0.84 (0.36) vs. 0.22 (0.09) mmol/l; P = 0.003], and the next morning IMTG concentration was approximately 30% greater [49.2 (6.6) vs. 38.3 (7.7) mmol/kg dry wt; P = 0.036] in Lipid compared with saline. However, muscle glycogen concentration was not different between trials (P = 0.82). Lipid caused a 24-h surplus of approximately 1100 kcal above energy balance (P = 0.00001), whereas energy balance was maintained in saline. Despite these differences in fatty acid and energy availability, Si the morning after exercise was not different between trials (P = 0.72). Thus insulin sensitivity the morning after a single exercise session was not reduced despite overnight exposure to a fourfold increase in plasma fatty acid concentration, elevated IMTG concentration, and systemic delivery of approximately 1,100-kcal excess.