Lysophosphatidylinositol-GPR55 signaling in the regulation of metabolism and cardiometabolic disorders

G protein coupled receptor 55 (GPR55) was initially identified as the orphan receptor and then suggested to be the atypical "non-CB1/non-CB2" cannabinoid receptor. However, later studies revealed that GPR55 is specific for lysophosphatidylinositol (LPI) synthesized from membrane phosphoinositides by phospholipases A1 or A2. Recent findings suggest that LPI-GPR55 signaling is involved in the pathogenesis of cardiometabolic disorders. GPR55 is expressed in adipose tissue, endothelial cells, inflammatory cells, and cardiomyocytes. Plasma LPI concentration and GPR55 expression in the adipose tissue are modified by nutritional status, leptin level and glucose tolerance. Ligand-activated GPR55 has anabolic effect in human adipose tissue, stimulates insulin secretion, induces hyperpolarization of endothelial cells, inhibits platelet aggregation, and increases Ca2+ concentration in cultured cardiomyocytes. In this review the recent findings about role of GPR55 signaling in adipose tissue, metabolic homeostasis and cardiovascular system are summarized.Adipobiology 2013; 5: 23-31

Hydrogen sulfide (H2S): the new member of gasotransmitter family

Recent studies indicate that apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third gaseous mediator in mammals. H2S is synthesized from L-cysteine by either cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), vitamin B6-dependent enzymes also involved in homocysteine metabolism. H2S stimulates ATP-sensitive potassium channels (KATP) in vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic β-cells. H2S is involved in neurotransmission, regulation of vascular tone and blood pressure, regulates gastrointestinal motility and secretory function and inhibits insulin secretion. Deficiency of endogenous H2S was observed in various models of arterial and pulmonary hypertension, gastric mucosal injury and liver cirrhosis. Exogenous H2S or its donors decrease blood pressure and reduce vascular hypertrophy in spontaneously hypertensive rats, inhibit neointima formation induced by arterial injury, ameliorate myocardial dysfunction associated with ischemia/reperfusion, and reduce gastric mucosal damage induced by anti-inflammatory drugs. On the other hand, excessive production of H2S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these diseases.Biomedical Reviews 2007; 18: 75-83

Up-regulation of vitamin D system in adipocytes by macrophage-derived factors: implications for (patho)physiology of adipose tissue

Vitamin D3 (cholecalciferol) plays an important role in calcium, phosphate, and bone metabolism. Vitamin D3, either synthesized endogenously or derived from alimentary sources, is first activated through sequential hydroxylations by vitamin D3 25-hydroxylase in the liver and 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1) in the kidney to 25-OH-D3 and 1,25(OH)2D3 (calcitriol), respectively. Calcitriol - the active vitamin D derivative - regulates calcium metabolism by acting on nuclear and extranuclear vitamin D receptors (VDR). Apart from mineral metabolism, vitamin D is involved in many other processes such as cell proliferation, inflammatory and immune reactions, glucose and lipid metabolism, etc. Indeed, VDR are expressed in virtually all tissues and vitamin D deficiency is suggested to contribute to the pathogenesis of various diseases including certain types of cancer, inflammatory bowel disease, multiple sclerosis, periodontal diseases, diabetes, hypertension, atherosclerosis and neurodegenerative diseases. In addition, vitamin D supplementation is beneficial in humans with at least some of these disorders and in animal experimental models of them.Adipobiology 2011; 3: 37-38

Effect of 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors (statins) on adipose tissue

Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting enzyme in cholesterol synthesis. Statins are widely used in the treatment of hypercholesterolemia and to reduce risk of acute cardiovascular and cerebrovascular events. Statins inhibit synthesis of not only cholesterol but also of non-steroid isoprenoids such as farnesyl- and geranylgeranylpyrophosphate, coenzyme Q (ubiquinone), dolichol, etc., which are involved in multiple cell metabolic and signaling cascades. Adipose tissue may be an important target for statins. Although statins have no effect on body weight and energy balance, they inhibit differentiation of preadipocytes to mature adipocytes and may induce adipocyte apoptosis. Stimulation of lipoprotein lipase in adipose tissue accelerates VLDL metabolism and may contribute to triglyceride-lowering effect of statins. According to some studies, statins reduce insulin sensitivity of adipose tissue and impair glucose metabolism in adipocytes. Statins also inhibit adipose tissue inflammation which plays an important role in obesity-associated pathologies. Finally, statins modulate production of adipokines such as leptin, adiponectin, resistin and visfatin. Currently available data suggest that effects on adipose tissue contribute to both beneficial and adverse consequences of statin therapy.Adipobiology 2009; 1: 35-50

Adipose tussue and homocysteine metabolism

Homocysteine (Hcy) is a non-protein aminoacid which is an intermediate of methionine metabolism. Elevated homocysteine level (hyperhomocysteinemia) is a risk factor of cardiovascular diseases. In addition, obesity and metabolic syndrome are associated with greater prevalence of atherosclerosis. The purpose of this article is to discuss the relationship between adipose tissue and Hcy metabolism. All enzymes involved in the synthesis and metabolism of Hcy are expressed in adipose tissue, and recent studies suggest that adipose tissue may be an important source of circulating homocysteine. The effect of obesity on Hcy level is controversial, however, most experimental and clinical studies indicate that Hcy is elevated in the metabolic syndrome in the absence of diabetes. Homocysteine elevation in the metabolic syndrome may result from either hyperinsulinemia or the impairment of renal function. In contrast, plasma Hcy is reduced in both type 1 and type 2 diabetes if renal function is normal, but becomes elevated when diabetic nephropathy develops. Leptin, which is markedly elevated in obese patients, has no effect on total plasma Hcy, but increases the level of homocysteine thiolactone - a cyclic thioester of homocysteine which plays an important role in complications of hyperhomocysteinemia. The effect of leptin is accounted for by the inhibition of  paraoxonase 1 (PON1) - the HDL-associated esterase, which hydrolyzes homocysteine thiolactone to Hcy. In addition, recent studies indicate that homocysteine may induce insulin resistance in adipose tissue by promoting endoplasmic reticulum stress and/or disrupting adipokine production; e.g. enhancing resistin and suppressing adiponectin.Biomedical Reviews 2009; 20: 7-15

Role of epidermal growth factor receptor in the pathogenesis and treatment of arterial hypertension

Epidermal growth factor receptor (EGFR) is a member of receptor tyrosine kinase family. Upon ligand binding, EGFR undergoes autophosphorylation at several tyrosine residues within its intracellular domain and triggers a number of signaling pathways including extracellular signal-regulated kinases, phospholipase Cγ, and phosphoinositide 3-kinase. EGFR regulates cell growth, proliferation and survival, and its overexpression or oncogenic mutations are observed in many human cancers. Therefore, several drugs have been developed to target EGFR for antitumor therapy. In the cardiovascular system, enhanced EGFR signaling is involved in vascular and myocardial hypertrophy. Recent studies suggest that EGFR may contribute to the development of arterial hypertension. Stimulated EGFR induces vasoconstriction and regulates renal tubular Na+ transport. Apart from its cognate ligand, EGFR is activated by many vasoconstrictors including angiotensin II, norepinephrine and endothelin-1. Enhanced EGFR signaling has been observed in several animal models of hypertension, and synthetic EGFR inhibitors reduce blood pressure in some of these models. Leptin, a peptide hormone which is produced by white adipose tissue and circulates in increased amounts in obese subjects, transactivates EGFR in vascular wall and the kidney, and EGFR inhibitor, AG1478, reduces blood pressure in experimental hyperleptinemia, suggesting that leptin-induced activation of EGFR may be involved in the pathogenesis of hypertension associated with the metabolic syndrome. These data suggest that inhibiting EGFR could be a novel therapeutic strategy for the treatment of hypertension. In addition, some of currently used hypotensive medications, in particular inhibitors of the renin-angiotensin-aldosterone system, modulate EGFR signaling.Biomedical Reviews 2007; 18: 1-26

Hydrogen sulfide: synthesis and function in the adipose tissue

Apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third gaseous mediator in mammals. H2S is synthesized from L-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), or by sequential action of alanine aminotransferase and 3-mercaptopyruvate sulfurtransferase. In the cardiovascular system, H2S is involved in the regulation of vascular tone and blood pressure, inhibits atherogenesis, and protects myocardium from ischemia-reperfusion injury. Recent studies indicate that H2S is synthesized also in the adipose tissue. Hydrogen sulfide produced in periadventitial adipose tissue (tunica adiposa) of the blood vessels induces vasodilation by activating K+ channels in smooth muscle cells. On the other hand, H2S inhibits basal and insulin-stimulated glucose uptake in visceral adipose tissue, and may be involved in the pathogenesis of insulin resistance. H2S production in periadventitial adipose tissue is stimulated by vasoconstrictors and aortic banding-induced hypertension and downregulated by aging. H2S signaling in adipose tissue may be affected by pharmacotherapy. Lipid-soluble statins (3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitors) increase H2S level in periadventitial adipose tissue and thus augment its anticontractile effect on the blood vessels. This effect of statins results from the depletion of ubiquinone - a component of mitochondrial respiratory chain - and the impairment of mitochondrial H2S oxidation.Adipobiology 2010; 2: 41-50

Leptin stimulates phosphoinositide 3-kinase in the vascular wall: role of ErbB receptors

Phosphoinositide 3-kinase (PI3K) phosphorylates phosphatidylinositol 4,5-diphosphate to phosphatidylinositol 3,4,5-triphosphate which then activates multiple intracellular signaling proteins such as protein kinase B (Akt), glycogen synthase kinase-3β, mammalian target of rapamycin (mTOR), etc. PI3K is involved in the regulation of vascular smooth muscle cell contractility, migration and proliferation - processes crucial for the pathogenesis of hypertension, atherosclerosis and restenosis. Increased leptin concentration in the metabolic syndrome contributes to the pathogenesis of cardiovascular diseases, but the effect of leptin on vascular smooth muscle cells is controversial. We examined the effect of experimentally induced hyperleptinemia on PI3K activity in the rat aortic media in adult male Wistar rats. Leptin, administered for 10 days in increasing dose (from 0.05 to 0.25 mg/kg every 12 hours), increased PI3K activity in the aortic media about 5-fold. The effect of leptin was markedly attenuated by epidermal growth factor receptor (EGFR) inhibitor, AG1478, as well as by the ErbB2 receptor inhibitor, AG825. In addition, leptin increased tyrosine phosphorylation of ErbB2, which was abolished by either AG1478 or AG825. These results indicate that hyperleptinemia increases the activity of vascular ErbB2 receptor in EGFR-dependent manner. In addition, both EGFR and ErbB2 contribute to PI3K stimulation by leptin. Activation of ErbB2 and PI3K may contribute to detrimental effects of leptin on vascular contractility and remodeling and may be involved, at least in part, in the relationship between metabolic syndrome and increased risk of vascular restenosis after angioplasty.Adipobiology 2011; 3: 53-59

Effect of experimental hyperhomocysteinemia on plasma lipid profile, insulin sensitivity and paraoxonase 1 in the rat

Hyperhomocysteinemia (hHcy) is a well-known risk factor of cardiovascular diseases, however, the mechanism of its detrimental effect is incompletely understood. Some studies suggest that, paradoxically, hHcy may promote traditional risk factors such as hyperlipidemia. We examined the effect of experimental hHcy on plasma lipid profile, glucose and insulin concentrations as well as on high-density lipoprotein (HDL)-associated antiatherosclerotic enzyme, paraoxonase 1 (PON1). Hyperhomocysteinemia was induced by feeding male Wistar rats with diet enriched with methionine or diet enriched in methionine and deficient in folate, vitamin B6 and B12 for 8 weeks. These diets resulted in the 3.3- and 9.6-fold elevation of plasma Hcy, respectively. Plasma total and HDL-cholesterol, triglycerides and apolipoprotein A-I were similar in all groups. High-methionine diets had no effect on fasting plasma glucose but significantly increased fasting plasma insulin concentration indicating impaired ability of insulin to suppress hepatic glucose output. PON1 activity was unchanged in high methionine vitamin B-sufficient diet-fed rats, but was decreased by 30-40% toward various substrates in high methionine vitamin B-deficient diet-fed animals. The results indicate that hHcy has no effect on lipid metabolism, however, induces insulin resistance and, above certain Hcy level, PON1 deficiency. Impaired insulin signaling and reduced PON1 activity may contribute to detrimental effects of hHcy.Adipobiology 2012; 4: 77-84

Leptin increases thromboxane A2 formation in the rat

Chronic hyperleptinemia may contribute to various complications of obesity including atherosclerosis, however, the underlying mechanisms are incompletely clear. We examined the effect of leptin on platelet activity by measuring stable metabolites of thromboxane A2 (TXA2), TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2, in plasma and urine. In vitro, leptin stimulated TXB2 formation by platelet-rich plasma (PRP). In vivo, leptin (1 mg/kg ip.) increased urinary excretion of 11-dehydro-TXB2 and 2,3-dinor-TXB2. Urinary excretion of these metabolites was also elevated in rats made hyperleptinemic by administration of recombinant leptin (0.5 mg/kg/day) for 8 days. The stimulatory effect of leptin on TXB2 formation in PRP isolated from hyperleptinemic animals was impaired in comparison to the control group. In rats made obese, hyperleptinemic and hyperinsulinemic/insulin resistant by cafeteria diet administered for 3 months, acute stimulatory effect of leptin on TXB2 formation by PRP was not impaired. In rats made insulin resistant by fructose feeding for 8 weeks, stimulatory effect of leptin on TXB2 formation in PRP was augmented in comparison to the control group. Insulin sensitizer, rosiglitazone, decreased insulin level and attenuated the stimulatory effect of leptin on TXB2 formation in obese and fructose-fed animals. In contrast, rosiglitazone had no effect on insulin level or leptin-induced TXB2 formation in control rats and rats receiving recombinant leptin for 8 days. These results indicate that: (i) leptin stimulates platelet TXA2 formation both in vitro and in vivo, (ii) chronic hyperleptinemia impairs acute stimulatory effect of leptin on platelet activity if insulin sensitivity is normal, (iii) insulin resistance/hyperinsulinemia augments the stimulatory effect of leptin on TXA2 formation, which results in normal platelet sensitivity to leptin in obesity associated with both hyperleptinemia and hyperinsulinemia, and (iv) PPAR-γ agonists such as rosiglitazone decrease platelet sensitivity to leptin by reducing insulin resistance.Adipobiology 2009; 1: 77-85