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There is increasing evidence that the metabolic state of the mother during pregnancy affects long-term glucose and lipid metabolism of the offspring. The liver X receptors (LXR)[alpha] and -[beta] are key regulators of cholesterol, fatty acid, and glucose metabolism. LXRs are activated by oxysterols and expressed in fetal mouse liver from day 10 of gestation onward. In the present study, we aimed to elucidate whether in utero pharmacological activation of LXR would influence fetal fatty acid and glucose metabolism and whether this would affect lipid homeostasis at adult age. Exposure of pregnant mice to the synthetic LXR agonist T0901317 increased hepatic mRNA expression levels of Lxr target genes and hepatic and plasma triglyceride levels in fetuses and dams. T0901317 treatment increased absolute de novo synthesis and chain elongation of hepatic oleic acid in dams and fetuses. T0901317 exposure in utero influenced lipid metabolism in adulthood in a sex-specific manner; hepatic triglyceride content was increased (+45%) in male offspring and decreased in female offspring (-42%) when they were fed a regular chow diet compared with untreated sex controls. Plasma and hepatic lipid contents and hepatic gene expression patterns in adult male or female mice fed a high-fat diet were not affected by T0901317 pretreatment. We conclude that LXR treatment of pregnant mice induces immediate effects on lipid metabolism in dams and fetuses. Despite the profound changes during fetal life, long-term effects appeared to be rather mild and sex selective without modulating the lipid response to a high-fat diet. fetus; lipid metabolism; gestation; long-term effects doi: 10.1152/ajpendo.00021.2009.

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 [+ or -] 7.2 vs. 12.1 [+ or -] 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 [+ or -] 13 vs. 176 [+ or -] 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 [+ or -] 1.0 vs. 14.3 [+ or -] 1.4 ml x [kg.sup.-1] x [min.sup.-1], P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fas in ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity. hepatic glucose production; hepatic steatosis; hyperinsulinemic euglycemic clamp; stable isotopes; triglycerides

In this study, we investigated in rats if hydroxycitric acid (HCA) reduces the postprandial glucose response by affecting gastric emptying or intestinal glucose absorption. We compared the effect of regulator HCA (310 mg/kg) and vehicle (control) on the glucose response after an intragastric or intraduodenal glucose load to investigate the role of altered gastric emptying. Steele's one-compartment model was used to investigate the effect of HCA on systemic glucose appearance after an intraduodenal glucose load, using [[U-.sup.13]C]-labeled glucose and D-[6,[6-.sup.2][H.sub.2]]-labeled glucose. Because an effect on postabsorptive glucose clearance could not be excluded, the effect of HCA on the appearance of enterally administered glucose in small intestinal tissue, liver, and portal and systemic circulation was determined by [[U-.sup.14]C]glucose infusion. Data show that HCA treatment delays the intestinal absorption of enterally administered glucose at the level of the small intestinal mucosa in rats. HCA strongly attenuated postprandial blood glucose levels after both intragastric (P < 0.01) and intraduodenal (P < 0.001) glucose administration, excluding a major effect of HCA on gastric emptying. HCA delayed the systemic appearance of exogenous glucose but did not affect the total fraction of glucose absorbed over the study period of 150 min. HCA treatment decreased concentrations of [[U-.sup.14]C]glucose in small intestinal tissue at 15 min after [[U-.sup.14]C]glucose administration (P < 0.05), in accordance with the concept that HCA delays the enteral absorption of glucose. These data support a possible role for HCA as food supplement in lowering postprandial glucose profiles. gastric emptying; Steele's one-compartment model; postprandial glucose response

Acetate, propionate, and butyrate are the main short-chain fatty acids (SCFAs) that arise from the fermentation of fibers by the colonic microbiota. While many studies focus on the regulatory role of SCFAs, their quantitative role as a catabolic or anabolic substrate for the host has received relatively little attention. To investigate this aspect, we infused conscious mice with physiological quantities of stable isotopes [1-13C]acetate, [2-13C]propionate, or [2,4-13C2]butyrate directly in the cecum, which is the natural production site in mice, and analyzed their interconversion by the microbiota as well as their metabolism by the host. Cecal interconversion, pointing to microbial cross-feeding, was high between acetate and butyrate, low between butyrate and propionate, and almost absent between acetate and propionate. As much as 62% of infused propionate was used in whole body glucose production, in line with its role as gluconeogenic substrate. Conversely, glucose synthesis from propionate accounted for 69% of total glucose production. The synthesis of palmitate and cholesterol in the liver was high from cecal acetate (2.8 and 0.7%, respectively) and butyrate (2.7 and 0.9%, respectively) as substrates, but low or absent from propionate (0.6 and 0.0%, respectively). Label incorporation due to chain elongation of stearate was approximately eightfold higher than de novo synthesis of stearate. Microarray data suggested that SCFAs exert a mild regulatory effect on the expression of genes involved in hepatic metabolic pathways during the 6-h infusion period. Altogether, gut-derived acetate, propionate, and butyrate play important roles as substrates for glucose, cholesterol, and lipid metabolism. [ABSTRACT FROM AUTHOR]