The pivotal role of liver X receptors (LXRs) in the metabolic conversion of cholesterol to bile acids in mice is well established. More recently, the LXRalpha promoter has been shown to be under tight regulation by peroxisome proliferator-activated receptors (PPARs), implying a role for LXRalpha in mediating the interplay between cholesterol and fatty acid metabolism. We have studied the role of LXR in fat cells and demonstrate that LXR is regulated during adipogenesis and augments fat accumulation in mature adipocytes. LXRalpha expression in murine 3T3-L1 adipocytes as well as in human adipocytes was up-regulated in response to PPARgamma agonists. Administration of a PPARgamma agonist to obese Zucker rats also led to increased LXRalpha mRNA expression in adipose tissue in vivo. LXR agonist treatment of differentiating adipocytes led to increased lipid accumulation. An increase of the expression of the LXR target genes, sterol regulatory binding protein-1 and fatty acid synthase, was observed both in vivo and in vitro after treatment with LXR agonists for 24 h. Finally, we demonstrate that fat depots in LXRalpha/beta-deficient mice are smaller than in age-matched wild-type littermates. These findings imply a role for LXR in controlling lipid storage capacity in mature adipocytes and point to an intriguing physiological interplay between LXR and PPARgamma in controlling pathways in lipid handling.

We studied the effects of thiazolidinedione treatment (rosiglitazone 1 or 10 micromol.kg(-1).day(-1) or darglitazone 1.3 micromol.kg(-1).day(-1) for 3 weeks) on lipid metabolism in obese Zucker rats. In the basal 7-h fasted state, rosiglitazone (10 micromol.kg(-1).day(-1)) and darglitazone corrected the hypertriglyceridemia by increasing plasma triglyceride (TG) clearance and decreasing hepatic TG production, as assessed using Triton WR 1339. Free fatty acid (FFA) metabolism was assessed using 3H-palmitate tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and tissue-specific nonoxidative FFA disposal (Rfs). Basal Ra, plasma FFA levels, and clearance were increased by both thiazolidinediones. Detailed studies were conducted with darglitazone, which under basal conditions increased Ra (+114%), Rox (+51%), and Rfs in adipose tissues. During euglycemic clamps performed at insulin levels corresponding to those observed postprandially, darglitazone increased the glucose infusion rate from 4.7 to 13.3 mg.min(-1) and, in contrast to the basal state, it decreased Ra (-67%), Rox (-84%), and Rfs in adipose tissue, muscle, and liver. We concluded that thiazolidinediones 1) ameliorate hypertriglyceridemia by lowered hepatic TG production and augmented TG clearance (two separate kinetic effects), 2) enhance insulin-mediated suppression of systemic FFA mobilization while increasing the capacity to mobilize FFA during fasting, 3) increase FFA trafficking into adipose tissue by increasing the ability of adipose tissue to take up and store FFA, and 4) enhance metabolic flexibility by improving glucoregulation under hyperinsulinemic conditions (possibly involving reduced skeletal muscle and liver exposure to fatty acids) and augmenting the capacity to utilize FFAs during fasting.

The present study was performed to assess the plasma and kidney levels of angiotensin I (ANG I) and ANG II during prehypertensive (4- to 5-wk old), development (6- to 8-wk old), and maintenance (10- to 12-wk old) phases of hypertension in pentobarbital-anesthetized transgenic rats [TGR; strain name: TGR(mRen2)27] and age-matched transgene-negative Hannover Sprague-Dawley rats (HanSD). At 4-5 wk, mean arterial pressures of TGR were not different from those of HanSD (110 +/- 5 vs. 114 +/- 4 mmHg). However, mean arterial pressures of 6-8 wk and 10-12 wk TGR were higher than those of HanSD (179 +/- 3 vs. 110 +/- 6 and 173 +/- 5 vs. 116 +/- 3 mmHg, respectively; P < 0.01 in both cases). Plasma ANG II levels in 4-5 wk and 6-8 wk TGR were not different from those in HanSD (70 +/- 11 vs. 66 +/- 7 and 60 +/- 8 vs. 48 +/- 12 fmol/ml, respectively). However, plasma ANG II levels in 10-12 wk TGR were higher than those in HanSD (125 +/- 26 vs. 38 +/- 12 fmol/ml, P < 0.01). Kidney ANG II levels in 4-5 wk, 6-8 wk, and 10-12 wk TGR averaged 370 +/- 57, 247 +/- 16, and 562 +/- 86 fmol/g, respectively, values not different from those in HanSD. In additional studies performed on 6-8 wk TGR and HanSD, multiple free-flow proximal tubular fluid collections were obtained and pooled for each animal. In these experiments, mean arterial pressures of the 10 TGR and 7 HanSD studied averaged 178 +/- 9 and 129 +/- 3 mmHg (P < 0.01), respectively. The ANG II concentration in proximal tubular fluid obtained from TGR averaged 5.6 +/- 2.1 pmol/ml (n = 10), a value not different from that in proximal tubular fluid collected from HanSD (5.3 +/- 2.8 pmol/ml, n = 7). However, the ANG II contents of the micropunctured left kidney and the nonmicropunctured right kidney of TGR were lower than those in HanSD (690 +/- 95 vs. 1,374 +/- 210 and 659 +/- 119 vs. 1,303 +/- 196 fmol/g, respectively; P < 0.01 in both cases). The present findings indicate that proximal tubular fluid of hypertensive TGR contains nanomolar concentrations of ANG II and that proximal tubular fluid, plasma and kidney ANG II levels in anesthetized hypertensive TGR are not markedly suppressed compared with those in normotensive control rats.

The present study was performed to evaluate renal vascular responsiveness (RVR) to ANG II in hypertensive transgenic rats [TGR; strain TGR(mRen2)27] harboring the mouse ren-2 renin gene. Renal blood flow (RBF) responses to either intravenous or intrarenal arterial administration of ANG II were assessed in pentobarbital sodium-anesthetized female heterozygous TGR (9–12 wk old) and age-matched transgene-negative Hanover Sprague-Dawley rats (HanSD). Intravenous bolus injections of 15 and 30 ng ANG II elicited dose-dependent increases in mean arterial blood pressure (AP) and decreases in RBF in both TGR and HanSD. However, the magnitude of the increases in AP was greater in TGR than in HanSD (24 ± 1 vs. 17 ± 2 mmHg and 33 ± 2 vs. 25 ± 1 mmHg, respectively, P < 0.05 in both cases). Similarly, the magnitude of the decrease in RBF elicited by intravenous administration of 15 ng of ANG II was greater in TGR than HanSD (−62 ± 3 vs. −52 ± 5%, P < 0.05). Intrarenal arterial administration of 1.5 and 3 ng ANG II did not alter mean AP in either group but elicited larger decreases in RBF in TGR than in HanSD (−24 ± 2 vs. −13 ± 1% and −41 ± 5 vs. −30 ± 2%, respectively, P< 0.05 in both cases). In contrast, intrarenal arterial administration of norepinephrine (40 and 80 ng) elicited smaller decreases in RBF in TGR than in HanSD (−24 ± 3 vs. −40 ± 6% and −51 ± 9 vs. −71 ± 8%, respectively, P < 0.05 in both cases), indicating that TGR do not exhibit a generalized increase in RVR to endogenous vasoconstrictors. Furthermore, the enhanced RVR to ANG II does not appear to reflect an impaired RVR to endogenous vasodilator factors since intrarenal administration of bradykinin and acetylcholine elicited larger increases in RBF in TGR than in HanSD. The present findings indicate that hypertensive TGR exhibit exaggerated renal and peripheral vascular responses to ANG II, which likely contributes to an increased renal and peripheral vascular resistance and thereby to the hypertension in TGR.