Davalintide (AC2307), a novel amylin-mimetic peptide: enhanced pharmacological properties over native amylin to reduce food intake and body weight.

Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide.

Research Design And Methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated.

Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes.

Plasma cholesteryl ester transfer protein (CETP) has a profound effect on neutral lipid transfers between HDLs and apolipoprotein B (apoB)-containing lipoproteins when it is expressed in combination with human apoA-I in HuAI/CETP transgenic (Tg) rodents. In the present study, human apoA-I-mediated lipoprotein changes in HuAI/CETPTg rats are characterized by 3- to 5-fold increments in the apoB-containing lipoprotein-to-HDL cholesterol ratio, and in the cholesteryl ester-to-triglyceride ratio in apoB-containing lipoproteins. These changes occur despite no change in plasma CETP concentration in HuAI/CETPTg rats, as compared with CETPTg rats.

Biological evaluation of 1-alkyl-3-phenylthioureas as orally active HDL-elevating agents.

A series of 1-alkyl-3-phenylthiourea analogues were prepared and evaluated as HDL- and Apo A-I-elevating and triglyceride-lowering agents. Several derivatives were superior to gemfibrozil. The optimal analogue (HDL376) was shown to raise HDL cholesterol in the rat, hamster, dog, and monkey models.

1-Hydroxyalkyl-3-phenylthioureas as novel HDL-elevating agents.

A series of 1-hydroxyalkyl-3-phenylthiourea analogs were prepared and evaluated as HDL-and Apo A-I-elevating agents. Derivatives 5h, 7j, 7n, and 7o were found to be as effective or superior to gemfibrozil.

Effects of peptide YY[3-36] on short-term food intake in mice are not affected by prevailing plasma ghrelin levels.

The gut-derived hormones peptide YY[3-36] (PYY[3-36]) and ghrelin are believed to influence similar hypothalamic circuits, albeit with opposing actions on energy balance. Thus, we carried out a series of studies to evaluate the interaction of these hormones on short-term food intake responses in mice. Intraperitoneal PYY[3-36] injection reduced short-term food intake by up to 50% in overnight-fasted mice and in postabsorptive animals during the early and late light cycle.

Effects of PYY[3-36] in rodent models of diabetes and obesity.

Background: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration.

Thiourea-based gemfibrozil analogues as HDL-elevating agents.

A series of gemfibrozil analogues with a thiourea moiety embedded in the side chain was prepared and evaluated as HDL-elevating agents. Derivatives 8b, 9b, 9c, and 9d were found to be approximately as effective as gemfibrozil (1) for HDL cholesterol elevation.

A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models.

A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1).

Peroxisome proliferator-activated receptor subtype-specific regulation of hepatic and peripheral gene expression in the Zucker diabetic fatty rat.

Fibrates and thiazolidinediones are used clinically to treat hypertriglyceridemia and hyperglycemia, respectively. Fibrates bind to the peroxisome proliferator-activated receptor (PPAR)-alpha, and thiazolidinediones are ligands of PPAR-gamma. These intracellular receptors form heterodimers with retinoid X receptor to modulate gene transcription.

Design and synthesis of 2-methyl-2-[4-(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic acids: a new class of dual PPARalpha/gamma agonists.

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.

Peroxisome proliferator-activated receptor (PPAR) gamma and retinoid X receptor (RXR) agonists have complementary effects on glucose and lipid metabolism in human skeletal muscle.

Aims/hypothesis: To determine the independent and potentially synergistic effects of agonists for PPAR gamma and RXR on glucose and lipid metabolism, as well as gene expression, in human skeletal muscle cell cultures.

Methods: Fully differentiated myotubes from non-diabetic subjects and subjects with Type II (non-insulin-dependent) diabetes mellitus were chronically (2 days) treated with LG100268 (4 mumol/l), an RXR agonist, or troglitazone (4.6 mumol/l), a PPAR gamma agonist or both, to determine the effects on glucose uptake, activity of glycogen synthase and palmitate oxidation.

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor.

A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well established animal model of atherosclerosis.

Accumulation of cholestatic lipoproteins in ANIT-treated human apolipoprotein A-I transgenic rats is diminished through dose-dependent apolipoprotein A-I activation of LCAT.

Administration of alpha-naphthylisothiocyanate (ANIT) to rats induces changes to plasma lipids consistent with cholestasis. We have previously shown (J. Lipid Res.

A selective peroxisome proliferator-activated receptor-gamma (PPARgamma) modulator blocks adipocyte differentiation but stimulates glucose uptake in 3T3-L1 adipocytes.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists such as the thiazolidinediones are insulin sensitizers used in the treatment of type 2 diabetes. These compounds induce adipogenesis in cell culture models and increase weight gain in rodents and humans. We have identified a novel PPARgamma ligand, LG100641, that does not activate PPARgamma but selectively and competitively blocks thiazolidinedione-induced PPARgamma activation and adipocyte conversion.

Skeletal muscle peroxisome proliferator- activated receptor-gamma expression in obesity and non- insulin-dependent diabetes mellitus.

Unlabelled: The two isoforms of peroxisome proliferator-activated receptor-gamma (PPARgamma1 and PPARgamma2), are ligand-activated transcription factors that are the intracellular targets of a new class of insulin sensitizing agents, the thiazolidinediones. The observation that thiazolidinediones enhance skeletal muscle insulin sensitivity in obesity and in patients with non-insulin-dependent diabetes mellitus (NIDDM), by activating PPARgamma, and possibly by inducing its expression, suggests that PPARgamma expression in skeletal muscle plays a key role in determining tissue sensitivity to insulin, and that PPARgamma expression may be decreased in insulin resistant subjects. We used a sensitive ribonuclease protection assay, that permits simultaneous measurement of the two isoforms, to examine the effects of obesity and NIDDM, and the effects of insulin, on skeletal muscle levels of PPARgamma1 and PPARgamma2 mRNA.

RXR agonists activate PPARalpha-inducible genes, lower triglycerides, and raise HDL levels in vivo.

Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are members of the intracellular receptor superfamily. PPARs bind to peroxisome proliferator-response elements (PPREs) as heterodimers with RXR and as such activate gene transcription in response to activators. Fibrates like gemfibrozil are well-known PPARalpha activators and are used in the treatment of hyperlipidemia.

Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates.

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism.

Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists.

Retinoic acid receptors (RAR), thyroid hormone receptors (TR), peroxisome proliferator activated receptors (PPARs) and the orphan receptor, LXR, bind preferentially to DNA as heterodimers with a common partner, retinoid X receptor (RXR), to regulate transcription. We investigated whether RXR-selective agonists replicate the activity of ligands for several of these receptors? We demonstrate here that RXR-selective ligands (referred to as rexinoids) function as RXR heterodimer-selective agonists, activating RXR: PPARgamma and RXR:LXR dimers but not RXR:RAR or RXR:TR heterodimers. Because PPARgamma is a target for antidiabetic agents, we investigated whether RXR ligands could alter insulin and glucose signalling.

Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists.

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPARgamma2 and hPPARgamma1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPARgamma activators. Human PPARgamma binds to DNA as a heterodimer with the retinoid X receptor (RXR).

Role of HDL phospholipid in efflux of cell cholesterol to whole serum: studies with human apoA-I transgenic rats.

Sera of transgenic rats expressing human apoA-I were tested for their ability to stimulate efflux of radiolabeled cholesterol from Fu5AH rat hepatoma cells. Expression of human apoA-I resulted in a dose-dependent increase in HDL, as measured by both HDL-cholesterol and HDL-phospholipid, and produced a decrease in rat apoA-I. In rats expressing high concentrations of human apoA-I (TgR[hAI]high, human apoA-I > 250 mg/dl), the increase in HDL-phospholipid was not proportional to the increase in human apoA-I, as illustrated by a HDL-PL/total apoA-I ratio of 0.

Effect of experimental nephrosis on hepatic lipoprotein secretion and urinary lipoprotein excretion in rats expressing the human apolipoprotein A-I gene.

When human apolipoprotein A-I was expressed in transgenic rats, induction of the nephrotic syndrome resulted in plasma A-I levels exceeding 10 mg/ml. Plasma lipids were no higher than in non-transgenic nephrotic rats. To explain this, the livers from four groups of rats were perfused: wild-type controls (WC), high expressor human apoA-I transgenic controls (TrGC), wild-type nephrotics (WN), and high expressor transgenic nephrotics (TrGN).

Overexpression of human apolipoprotein A-I in transgenic rats and the hyperlipoproteinemia associated with experimental nephrosis.

Hyperlipoproteinemia contributes both to kidney disease progression and the development of atherosclerosis. Elevated high density lipoprotein cholesterol and apolipoprotein A-I (apoA-I) serum levels are independent factors protective against the atherosclerotic process. We examined the effects in a transgenic rat model of human apoA-I expression on the hyperlipoproteinemia and edema after puromycin aminonucleoside-induced nephrosis in three groups of animals: low line (TgR[hAI]low, human plasma apoA-I = 16.

High level expression of human apolipoprotein A-I in transgenic rats raises total serum high density lipoprotein cholesterol and lowers rat apolipoprotein A-I.

To examine the consequences of increased apolipoprotein A-I production on cholesterol and lipoprotein metabolism, we have produced two lines of transgenic rats; one expressing moderate and one very high levels of human apolipoprotein A-I. The rats were produced by microinjection of a 13 kbp DNA fragment containing the human apolipoprotein A-I gene plus 10 kbp of its 5' flanking sequence and 1 kbp of its 3' flanking sequence. Both lines of transgenic rats express human apolipoprotein A-I mRNA in liver and human apolipoprotein A-I in plasma.

Nonimmunochemical quantitation of mammalian apolipoprotein A-I in whole serum or plasma by nonreducing gel electrophoresis.

A rapid and convenient method for the quantitation of mammalian apoA-I has been developed. The method involves nonreducing sodium dodecyl sulfate gel electrophoresis and Coomassie blue staining, and takes advantage of the relative abundance of apoA-I in whole serum or plasma. ApoA-I was sufficiently resolved to allow quantitation by laser densitometry or spectrophotometry.