Antilipolytic Effect Research Articles

Dipeptidyl peptidase-IV (DPP-IV) inhibitors enhance the paracrine antilipolytic effects of neuropeptide Y (NPY),

Dipeptidyl peptidase-IV (DPP-IV) inhibitors enhance the paracrine antilipolytic effects of neuropeptide Y (NPY),

Chronic Ethanol and Triglyceride Turnover in White Adipose Tissue in Rats: INHIBITION OF THE ANTI-LIPOLYTIC ACTION OF INSULIN AFTER CHRONIC ETHANOL CONTRIBUTES TO INCREASED TRIGLYCERIDE DEGRADATION

Chronic ethanol consumption disrupts whole-body lipid metabolism. Here we tested the hypothesis that regulation of triglyceride homeostasis in adipose tissue is vulnerable to long-term ethanol exposure. After chronic ethanol feeding, total body fat content as well as the quantity of epididymal adipose tissue of male Wistar rats was decreased compared with pair-fed controls. Integrated rates of in vivo triglyceride turnover in epididymal adipose tissue were measured using (2)H(2)O as a tracer. Triglyceride turnover in adipose tissue was increased due to a 2.3-fold increase in triglyceride degradation in ethanol-fed rats compared with pair-fed controls with no effect of ethanol on triglyceride synthesis. Because increased lipolysis accompanied by the release of free fatty acids into the circulation is associated with insulin resistance and liver injury, we focused on determining the mechanisms for increased lipolysis in adipose tissue after chronic ethanol feeding. Chronic ethanol feeding suppressed beta-adrenergic receptor-stimulated lipolysis in both in vivo and ex vivo assays; thus, enhanced triglyceride degradation during ethanol feeding was not due to increased beta-adrenergic-mediated lipolysis. Instead, chronic ethanol feeding markedly impaired insulin-mediated suppression of lipolysis in conscious rats during a hyperinsulinemic-euglycemic clamp as well as in adipocytes isolated from epididymal and subcutaneous adipose tissue. These data demonstrate for the first time that chronic ethanol feeding increased the rate of triglyceride degradation in adipose tissue. Furthermore, this enhanced rate of lipolysis was due to a suppression of the anti-lipolytic effects of insulin in adipocytes after chronic ethanol feeding.

Niacin in cardiovascular prevention: mechanisms, efficacy, and safety

This review describes niacin's mechanism of action, efficacy in cardiovascular prevention, and safety. A G-protein-coupled receptor [GPR109A/HM74A, mouse PUMA-G (protein upregulated in macrophages by interferon-gamma)] was found to mediate the antilipolytic effect of niacin via inhibition of adenylyl cyclase in adipocytes. The same receptor in skin Langerhans cells mediates the common flushing side effect. The endogenous ligand for the receptor may be beta-hydroxybutyrate. Among nine controlled clinical trials using niacin, mostly combined with other drugs, statistically significant positive impact on clinical or anatomic cardiovascular end-points was found in seven, which represents a remarkably consistent record of benefit. Although niacin induces insulin resistance, deterioration of glycemic control in diabetes is usually minor, and there is no evidence of increased incidence of new onset diabetes. Hepatic toxicity is common with higher doses of sustained-release niacin but rare with immediate-release and extended-release niacin at doses up to 2000 mg/day. Extended-release and immediate-release niacin do not substantially potentiate myopathic effects when given in combination with statins. Recently developed understanding of the mechanisms, efficacy, and safety of niacin, along with progress in reducing the chief side effect of flushing, should enhance the use of this valuable agent for cardiovascular prevention.

Comparison of rat and dog models of vasodilatation and lipolysis for the calculation of a therapeutic index for GPR109A agonists

Introduction GPR109A is the receptor mediating both the antilipolytic and vasodilatory effects of nicotinic acid. In order to develop agonists for GPR109A with improved therapeutic indices we have sought to optimize animal models that evaluate both nicotinic acid-mediated inhibition of lipolysis and stimulation of vasodilatation. The rat and the dog have previously been used to study the antilipolytic effects of nicotinic acid, but no optimal vasodilatation model exits in either species. Methods We have developed a vasodilatation model in the rat that measures changes in ear perfusion using laser Doppler flowmetry. In the dog, we have developed a model of vasodilatation measuring changes in red color values in the ear, using a spectrocolorimeter. Effects of GPR109A agonists on lipolysis were measured in both species after oral dosing of compounds, and measuring plasma levels of free fatty acids. Results In both rat and dog, GPR109A agonists induce dose- and time-dependent vasodilatation, similar to that observed in humans. Vasodilatation is inhibited in both species with cyclooxygenase inhibitors or a specific DP1 receptor antagonist, indicating that, as in man, nicotinic acid-induced vasodilatation in rats and dogs is mainly mediated by the release of PGD 2. Discussion Our results show that both rat and dog are useful models for the characterization of GPR109A agonists. A therapeutic index for GPR109A agonists can be calculated in either species.

Mechanism of Increased Lipolysis in Cancer Cachexia

Loss of fat mass is a key feature of cancer cachexia and has been attributed to increased adipocyte lipolysis. The mechanism behind this alteration is unknown and was presently investigated. We studied mature s.c. fat cells and differentiated preadipocytes from 26 cancer patients with and without cachexia. Hormone-induced lipolysis and expression of lipolysis-regulating genes were determined together with body composition and in vivo lipolytic activity (fasting plasma glycerol or fatty acids related to body fat). Body fat was reduced by 40% and in vivo lipolytic activity was 2-fold increased in cachexia (P = 0.001). In mature adipocytes, the lipolytic effects of catecholamines and natriuretic peptide were 2- to 3-fold increased in cachexia (P < 0.001). This was completely counteracted by inhibiting the rate-limiting lipolysis enzyme hormone-sensitive lipase (HSL). In cachexia, the expression levels of HSL mRNA and protein were increased by 50% and 100%, respectively (P = 0.005-0.03), which strongly correlated with in vitro lipolytic stimulation (r = 0.7-0.9). The antilipolytic effect of insulin in mature fat cells and the stimulated lipolytic effect in differentiated preadipocytes were unaltered in cachexia. Patients who lost weight due to other factors than cancer cachexia had no change in adipocyte lipolysis. In conclusion, adipocyte lipolysis is increased in cancer cachexia not due to nonepigenic factors or to weight loss per se, but most probably because of enhanced expression and function of adipocyte HSL. The selective inhibition of this enzyme may prevent fat loss in cancer patients.

Obesity and Atherogenic Dyslipidemia

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

Antilipolytic effect of calcium sensing receptor activation in human adipocytes

Antilipolytic effect of calcium sensing receptor activation in human adipocytes

Health risks associated with overweight and obesity

The intra-abdominal visceral deposition of adipose tissue,which characterizes upper body – central – obesity(assessed by waist circumference and/or waist : hip ratio)is a major contributor to the development of hypertension,elevated plasma insulin concentrations and insulin resis-tance, hyperglycaemia and hyperlipidaemia (metabolic syn-drome). The concept of the metabolic syndrome refers tothe phenomenon of risk-factor clustering – a collection ofmetabolic traits occurring in the same individual with theclustering presumably reflecting a unifying underlyingpathophysiology that requires a holistic approach to theirmanagement (5–7).Many of the health risks associated with increasing bodyweight begin to appear in children and young people. Ofgreat concern is the increasing prevalence of type 2 diabetesand associated medical complications in childhood (8–10).This early onset needs to be reflected by active managementand research priorities to reduce the consequential healthand economic burdens (11).

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

Elevated lipolysis and circulating free fatty acid (FFA) levels have been linked to the pathogenesis of insulin resistance. A1 adenosine receptor agonists are potent inhibitors of lipolysis. Several A1 agonists have been tested as potential antilipolytic agents; however, their effect on the cardiovascular system remains a potential problem for development of these agents as drugs. In the present study, we report that CVT-3619 [(2-{6-[((1R,2R)-2-hydroxycyclopentyl) amino] purin9-yl} (4S,5 S,2R,3R)5-[(2fluorophenylthio) methyl] oxolane-3,4-diol)], a novel partial A1 receptor agonist, significantly reduces circulating FFA levels without any effect on heart rate and blood pressure in awake rats. Rats were implanted with indwelling arterial and venous cannulas to obtain serial blood samples, record arterial pressure, and administer drug. CVT-3619 decreased FFA levels in a dose-dependent manner at doses from 1 up to 10 mg/kg. The FFA-lowering effect was blocked by the A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. Triglyceride (TG) levels were also significantly reduced by CVT-3619 treatment in the absence and presence of Triton. Tachyphylaxis of the antilipolytic effect of CVT-3619 (1 mg/kg i.v. bolus) was not observed with three consecutive treatments. An acute reduction of FFA by CVT-3619 was not followed by a rebound increase of FFA as seen with nicotinic acid. The potency of insulin to decrease lipolysis was increased 4-fold (p < 0.01) in the presence of CVT-3619 (0.5 mg/kg). In summary, CVT-3619 is an orally bioavailable A1 agonist that lowers circulating FFA and TG levels by inhibiting lipolysis. CVT-3619 has antilipolytic effects at doses that do not elicit cardiovascular effects.

Dynamic Modeling of Free Fatty Acid, Glucose, and Insulin: An Extended "Minimal Model"

The mathematical models for patients with diabetes proposed in the literature since the late 1970s are mainly glucocentric (glucose-based); hence, the contribution of free fatty acid (FFA) metabolism in the body and its glucose-insulin interactions have been largely ignored. However, approximately 90% of the muscle energy is derived from FFA metabolism when the body is at rest. Furthermore, significant interactions exist among FFA, glucose, and insulin. With the long-term goal of developing a closed-loop glucose control system, a model of the major energy-providing substrate dynamics is required. The Bergman minimal model was extended to include plasma FFA dynamics, and its interaction with glucose and insulin dynamics, with a primary focus on patients with Type 1 diabetes. Differential equations were developed for plasma FFA concentrations and "remote" FFA effects on glucose uptake, as well as "remote" insulin effects on plasma FFA concentrations. Parameters for the model were estimated from experimental data provided in the scientific literature. The minimal model was extended in order to capture three major metabolic aspects: the antilipolytic effect of insulin; the lipolytic effect of prolonged hyperglycemia; and the impairing effect of FFA on glucose uptake rate. The dynamic fit of glucose, FFA, and insulin profiles is consistent with published data. The extended minimal model successfully captured the plasma FFA concentration behavior, the plasma insulin and glucose concentrations, and the physiological interactions that exist among these species. This more comprehensive description of energy-providing substrate dynamics may provide a novel simulation test-bed for analysis of patients with insulin dependent diabetes and controller design.

Entwicklung des Körpergewichts unter antidiabetischer Therapie

Antidiabetic treatment of persons with type I or 2 diabetes mellitus is usually accompanied by body-weight gain. This is because any improvement in metabolism is associated with a decrease in glycosuria: Long-persisting loss of calories via urine is decreased. Furthermore, insulin has an antilipolytic effect simulates lipogenesis and promotes fluid retention. Hypoglycemia always necessitates additional intake of carbohydrates and thus also favors weight gain. During antidiabetic treatment with metformin the increase in body weight is significantly less than during treatment with sulphonylurea compounds or insulin. For this reason metformin is the drug of choice in the antidiabetic treatment of overweight diabetics. It is also superior to all other drugs when given together with insulin. The best results of insulin treatment with regard to weight control are obtained with basal insulin combined with metformin rather than insulin alone, prandial insulin substitution or intensified insulin treatment. If the aim is weight reduction, the pharmacokinetics of short-acting insulin analogs makes adaptation of insulin dose to reduced food intake easier than normal insulin. More attention than has previously been the case should be paid from the start to measures that prevent weight gain when planning antidiabetic treatment: prevention of weight gain is easier to achieve than weight reduction.

Hypermetabolism of Fat in V1a Vasopressin Receptor Knockout Mice

[Arg8]Vasopressin (AVP) has an antilipolytic action on adipocytes, but little is known about the mechanisms involved. Here, we examined the involvement of the V1a receptor in the antilipolytic effect of AVP using V1a receptor-deficient (V1aR-/-) mice. The levels of blood glycerol were increased in V1aR-/- mice. The levels of ketone bodies, such as acetoacetic acid and 3-hydroxybutyric acid, the products of the lipid metabolism, were increased in V1aR-/- mice under a fasting condition. Triacylglyceride and free fatty acid levels in blood were decreased in V1aR-/- mice. Furthermore, measurements with tandem mass spectrometry determined that carnitine and acylcarnitines in serum, the products of beta-oxidation, were increased in V1aR-/- mice. Most acylcarnitines were increased in V1aR-/- mice, especially in the case of 2-carbon (C2), C10:1, C10, C14:1, C16, C18:1, and hydroxy-18:1-carbon (OH-C18:1)-acylcarnitines under feeding rather than under fasting conditions. The analysis of tissue C2-acylcarnitine level showed that beta-oxidation was promoted in muscle under the feeding condition and in liver under the fasting condition. An in vitro assay using brown adipocytes showed that the cells of V1aR-/- mice were more sensitive to isoproterenol for lipolysis. These results suggest that the lipid metabolism is enhanced in V1aR-/- mice. The cAMP level was enhanced in V1aR-/- mice in response to isoproterenol. The phosphorylation of Akt by insulin stimulation was reduced in V1aR-/- mice. These results suggest that insulin signaling is suppressed in V1aR-/- mice. In addition, the total bile acid, taurine, and cholesterol levels in blood were increased, and an enlargement of the cholecyst was observed in V1aR-/- mice. These results indicated that the production of bile acid was enhanced by the increased level of cholesterol and taurine. Therefore, these results indicated that AVP could modulate the lipid metabolism by the antilipolytic action and the synthesis of bile acid via the V1a receptor.

Prevention of Adipose Tissue Depletion during Food Deprivation in Angiotensin Type 2 Receptor-Deficient Mice

Angiotensin (Ang) II is produced locally in various tissues, but its role in the regulation of tissue metabolism is still unclear. Recent studies have revealed the role of type 2 Ang II receptor (AT2R) in the control of energy homeostasis and lipid metabolism. The contribution of the AT2R to adaptation to starvation was tested using AT2R-deficient (AT2R (y)(/-)) mice. Fasted AT2R (y)(/-) mice exhibited a lower loss of adipose tissue weight associated to a decreased free fatty acid (FFA) release from stored lipids than the controls. In vitro studies show that Ang II causes an AT1R-mediated antilipolytic effect in isolated adipocytes. AT1R expression is up-regulated by fasting in both genotypes, but the increase is more pronounced in AT2R (y/-) mice. In addition, the increased muscle beta-oxidation displayed in AT2R (y/-) mice on a fed state, persists after fasting compared with wild-type mice. In liver from fed mice, AT2R deficiency did not modify the expression of genes involved in fatty acid oxidation. However, in response to fasting, the large increase of the expression of this subset of genes exhibited by wild-type mice, was impaired in AT2R (y/-) mice. Taken together, decreased lipolytic capacity and increased muscle fatty acid oxidation participate in the decreased plasma FFA observed in fasted AT2R (y/-) mice and could account for the lower FFA metabolism in the liver. These data reveal an important physiological role of AT2R in metabolic adaptations to fasting.

Hormonal Control of Reversible Translocation of Perilipin B to the Plasma Membrane in Primary Human Adipocytes

In adipocytes, perilipin coats and protects the central lipid droplet, which stores triacylglycerol. Alternative mRNA splicing gives rise to perilipin A and B. Hormones such as catecholamines and insulin regulate triacylglycerol metabolism through reversible serine phosphorylation of perilipin A. It was recently shown that perilipin was also located in triacylglycerol-synthesizing caveolae of the plasma membrane. We now report that perilipin at the plasma membrane of primary human adipocytes was phosphorylated on a cluster of threonine residues (299, 301, and 306) within an acidic domain that forms part of the lipid targeting domain. Perilipin B comprised <10% of total perilipin but was the major isoform associated with the plasma membrane of human adipocytes. This association was controlled by insulin and catecholamine: perilipin B was specifically depleted from the plasma membrane in response to the catecholamine isoproterenol, while insulin increased the amount of threonine phosphorylated perilipin at the plasma membrane. The reversible translocation of perilipin B to and from the plasma membrane in response to insulin and isoproterenol, respectively, suggests a specific function for perilipin B to protect newly synthesized triacylglycerol in the plasma membrane.

Mechanism of nicotinic acid‐induced cutaneous vasodilation

GPR109A (HM74A in humans and PUMA-G in mice) has been recently identified as a nicotinic acid (NA) receptor and to mediate the anti-lipolytic effect of NA. In order to clarify the mechanism of NA-induced flushing cutaneous blood flow was determined in the mouse ear using laser-Doppler flowmetry. Intraperitoneal injection of 200 mg/kg NA resulted in a transient biphasic increase in blood flow, which started within 2 min after administration and was not accompanied by any measurable change in blood pressure. Mice lacking the PUMA-G receptor did not show the flushing response. NA-induced flushing was also abrogated in the absence of cyclooxygenase-1. In addition, NA-induced flushing remained unaltered in prostacyclin receptor deficient mice but reduced significantly in mice lacking the prostaglandin D2 (PGD2) or prostaglandin E2 (PGE2) receptors. Northern blot analysis showed that PUMA-G is expressed in the external ear and RT-PCR revealed expression of PUMA-G in dendritic cells of the ear skin. Finally, we tested whether bone marrow transplantation to PUMA-G-deficient animals may rescue the flushing response. Three months after transplantation PUMA-G-/- mice, which had received wild type bone marrow, started to show flushing in response to NA. Our data clearly indicate that the NA-receptor on bone marrow derived cells mediates NA-induced flushing, and that this effect involves release of PGD2 and PGE2 most likely from immune cells of the skin. Grant support: DFG, OTKA.

Effect of Endothelin‐1 on Lipolysis in Rat Adipocytes

To explore the role of endothelin-1 (ET-1) on lipid metabolism, we examined the effect of ET-1 on lipolysis in rat adipocytes. Adipocytes isolated from male Sprague-Dawley rats, weighing 400 to 450 grams, were incubated in Krebs-Ringer buffer with or without 10(-7) M ET-1 for various times or with various concentrations of ET-1 for 4 hours; then glycerol release into the incubation medium was measured. In addition, selective ET(A)R and ET(B)R blockers were used to identify the ET receptor subtype involved. We also explored the involvement of cyclic adenosine monophosphate (cAMP) in ET-1-stimulated lipolysis using an adenylyl cyclase inhibitor and by measuring changes in intracellular cAMP levels in response to ET-1 treatment. To further explore the underlying mechanism of ET-1 action, we examined the involvement of the extracellular signal-regulated kinase (ERK)-mediated pathways. Our results showed that ET-1 caused lipolysis in rat adipocytes in a time- and dose-dependent manner. BQ610, a selective ET(A)R blocker, blocked this effect. The adenylyl cyclase inhibitor, 2',5'-dideoxyadenosine, had no effect on ET-1-stimulated lipolysis. ET-1 did not induce an increase in intracellular cAMP levels. In addition, ET-1-induced lipolysis was blocked by inhibition of ERK activation using PD98059. Coincubation of cells with ET-1 and insulin suppressed ET-1-stimulated lipolysis. These findings show that ET-1 stimulates lipolysis in rat adipocytes through the ET(A)R and activation of the ERK pathway. The underlying mechanism is cAMP-independent. However, this non-conventional lipolytic effect of ET-1 is inhibited by the anti-lipolytic effect of insulin.

Ginseng Extract Inhibits Lipolysis in Rat Adipocytes In Vitro by Activating Phosphodiesterase 4

Elevated concentrations of plasma free fatty acids (FFA) may cause insulin resistance. Inhibition of lipolysis reduces FFA availability and improves insulin sensitivity. Ginseng extract (Panax spp., GE) was shown to improve glycemia in Type 2 diabetes. In the present study, the antilipolytic effect of GE in rat adipocytes and the signaling pathway for GE antilipolysis were investigated. Adipocytes were isolated from rat fat tissue by collagenase digestion. The ability of GE to inhibit lipolysis was assessed by measuring glycerol and FFA release into the incubation medium. Phosphatidylinositol 3-kinase (PI3-K) inhibitor and various phosphodiesterase (PDE) inhibitors were applied to investigate the signaling pathway for GE antilipolysis. The present study showed that insulin and GE inhibited lipolysis by 42.4 and 49% compared with basal, respectively (P < 0.05). Unlike insulin, the PI3-K inhibitor wortmannin did not reverse GE antilipolysis, and GE did not affect phosphorylation of protein kinase B (PKB). The nonselective PDE inhibitor enprofylline reversed both insulin and GE antilipolysis. The specific phosphodiesterase 3 (PDE3) inhibitor cilostamide reversed insulin antilipolysis completely, but did not significantly affect GE antilipolysis. The specific phosphodiesterase 4 (PDE4) inhibitor rolipram did not significantly affect insulin antilipolysis, but almost completely reversed GE antilipolysis. Moreover, the combination of PDE3 and PDE4 inhibitors completely reversed GE antilipolysis. None of the ginsenosides (Rb1, Re, Rg1, Rc, Rb2, and Rd) were responsible for GE antilipolysis. The results suggest that ginseng exerts its antilipolytic effect through a signaling pathway different from that of insulin. GE antilipolysis is mediated in part by activating PDE4 in rat adipocytes.

Niacin induces PPARγ expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways

HM74 and HM74a have been identified as receptors for niacin. HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation. In macrophages, niacin induces peroxisome proliferator-activated receptor γ (PPARγ)-dependent and cAMP-dependent expression of genes mediating reverse cholesterol transport, although via an unidentified receptor. We describe constitutive expression of HM74a mRNA and hypoxia- and IFNγ-inducible expression of HM74 and HM74a in human monocytic cell lines and primary cells in culture. In U937 cells niacin-induced expression of 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2), the most potent endogenous ligand of PPARγ. Both niacin and the structurally distinct HM74/HM74a ligand acifran-induced nuclear expression of PPARγ protein and enhanced PPARγ transcriptional activity. Niacin-induced PPARγ transcriptional activity was pertussis toxin sensitive and required activity of phospholipase A 2 (EC 3.1.1.4), cyclo-oxygenase (EC 1.14.99.1) and prostaglandin D 2 synthase (EC 5.3.99.2). Niacin also induced PPARγ transcriptional activity in HM74 and HM74a CHO cell transfectants, although not in vector-only control cells. This was sensitive to pertussis toxin and to inhibition of phoshoplipase A 2 and cyclo-oxygenase activity. Additionally, niacin increased intracellular cAMP in U937 via a pertussis toxin and cyclo-oxygenase-sensitive mechanism. These results indicate that HM74 and HM74a can mediate macrophage responses to niacin via activation of the prostaglandin synthesis pathway and induction and activation of PPARγ. This suggests a novel mechanism(s) mediating the clinical effects of pharmacological doses of niacin.

GPR109A (PUMA-G/HM74A) mediates nicotinic acid–induced flushing

Nicotinic acid (niacin) has long been used as an antidyslipidemic drug. Its special profile of actions, especially the rise in HDL-cholesterol levels induced by nicotinic acid, is unique among the currently available pharmacological tools to treat lipid disorders. Recently, a G-protein-coupled receptor, termed GPR109A (HM74A in humans, PUMA-G in mice), was described and shown to mediate the nicotinic acid-induced antilipolytic effects in adipocytes. One of the major problems of the pharmacotherapeutical use of nicotinic acid is a strong flushing response. This side effect, although harmless, strongly affects patient compliance. In the present study, we show that mice lacking PUMA-G did not show nicotinic acid-induced flushing. In addition, flushing in response to nicotinic acid was also abrogated in the absence of cyclooxygenase type 1, and mice lacking prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)) receptors had reduced flushing responses. The mouse orthologue of GPR109A, PUMA-G, is highly expressed in macrophages and other immune cells, and transplantation of wild-type bone marrow into irradiated PUMA-G-deficient mice restored the nicotinic acid-induced flushing response. Our data clearly indicate that GPR109A mediates nicotinic acid-induced flushing and that this effect involves release of PGE(2) and PGD(2), most likely from immune cells of the skin.

Regulation of lipolysis in isolated adipocytes of rainbow trout ( Oncorhynchus mykiss): The role of insulin and glucagon

In the present study, we have examined the effects of insulin and glucagon on the lipolysis of rainbow trout ( Oncorhynchus mykiss). To this end, adipocytes were isolated from mesenteric fat and incubated in the absence (basal lipolysis) or presence of different concentrations of insulin and glucagon. In addition, to further elucidate the effects of these hormones in vivo on adipocyte lipolysis, both fasting and intraperitoneal glucagon injection experiments were performed. Basal lipolysis, measured as the glycerol released in the adipocyte medium, increased proportionally with cell concentration and incubation time. Cell viability was verified by measuring the release of lactate dehydrogenase (LDH) activity in the medium. Insulin (at doses of 35 and 350 nM) decreased lipolysis in isolated adipocytes of rainbow trout in vitro, while glucagon was clearly lipolytic at concentrations of 10 and 100 nM. Furthermore, hypoinsulinemia induced by fasting, as well as glucagon injection, significantly increased lipolysis in isolated adipocytes approximately 1.5- and 1.4-fold, respectively, when compared with adipocytes from control fish. Our data demonstrate that lipolysis, as measured in isolated adipocytes of rainbow trout, can be regulated by both insulin and glucagon. These results not only indicate that insulin is an important hormone in lipid deposition via its anti-lipolytic effects on rainbow trout adipocytes, but also reveal glucagon as a lipolytic hormone, as shown by both in vitro and in vivo experiments.