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PubMed2003

Bilayer localization of membrane-active peptides studied in biomimetic vesicles by visible and fluorescence spectroscopies.

Depth of bilayer penetration and effects on lipid mobility conferred by the membrane-active peptides magainin, melittin, and a hydrophobic helical sequence KKA(LA)7KK (denoted KAL), were investigated by colorimetric and time-resolved fluorescence techniques in biomimetic phospholipid/poly(diacetylene) vesicles. The experiments demonstrated that the extent of bilayer permeation and peptide localization within the membrane was dependent upon the bilayer composition, and that distinct dynamic modifications were induced by each peptide within the head-group environment of the phospholipids. Solvent relaxation, fluorescence correlation spectroscopy and fluorescence quenching analyses, employing probes at different locations within the bilayer, showed that magainin and melittin inserted close to the glycerol residues in bilayers incorporating negatively charged phospholipids, but predominant association at the lipid-water interface occurred in bilayers containing zwitterionic phospholipids. The fluorescence and colorimetric analyses also exposed the different permeation properties and distinct dynamic influence of the peptides: magainin exhibited the most pronounced interfacial attachment onto the vesicles, melittin penetrated more into the bilayers, while the KAL peptide inserted deepest into the hydrophobic core of the lipid assemblies. The solvent relaxation results suggest that decreasing the lipid fluidity might be an important initial factor contributing to the membrane activity of antimicrobial peptides.

Antimicrobial Cationic Peptides↗
PubMed1991

Lipolytic activity in adipose tissue of mice bearing Ehrlich ascites carcinoma.

The hormonal background of lipid mobilization in mice bearing Ehrlich ascites tumor (EAT) was investigated. Glycerol production rates were measured in adipose tissues from healthy and tumor-bearing (TB) animals being in early and late stages of tumor growth. The basal rate of lipolysis was enhanced significantly in the epididymal fat pads from mice with EAT. The catecholamine- and theophylline-stimulated activity was also higher in the tumorous animals, and the hormone-stimulated lipolysis was more effectively repressed by insulin and propranolol in adipose tissue from TB mice, compared to healthy ones. Susceptibility of adipose tissues to hormonal manipulations suggested that an imbalance in the concentration of lipolytic and antilipolytic hormones in the blood might promote the lipid depletion in the TB host organism. The low glucose and insulin concentrations and high catecholamine levels found in the sera of the tumorous animals seem to support this conception.

Adipose Tissue↗
PubMed1993

Beta 3-adrenoceptors in dog adipose tissue: studies on their involvement in the lipomobilizing effect of catecholamines.

The existence of beta 3-adrenoceptors in adipose tissue and their involvement in the control of lipolysis was investigated in dog. Selective beta 3-adrenergic agonists (BRL 37344, SR 58611A and CGP 12177) and catecholamines (isoproterenol and norepinephrine) activated lipolysis in isolated adipocytes (order of potency: isoproterenol > BRL 37344 > norepinephrine > CGP 12177 > SR 58611A). The lipolytic effect of 0.05 microM BRL 37344 was antagonized by the nonselective beta-AR antagonists, but the selective beta 1-(CGP 20712A) and beta 2-(ICI 118551) antagonists were ineffective. Infused to conscious dogs, beta 3-adrenergic agonists increased plasma nonesterified fatty acids levels with an order of potency equivalent to that defined in lipolysis. The lipomobilizing effect induced by the administration of an alpha 2-antagonist (0.01 mg/kg RX 821002 i.v.) was suppressed by bupranolol (0.5 mg/kg) or the combination of CGP 20712A and ICI 118551 (0.25 mg/kg each). The effect of 0.05 mg/kg RX 821002 was only partially suppressed by the same beta-antagonist combination, whereas bupranolol totally abolished it. At 0.5 mg/kg, the RX 821002 effect was not modified by beta-antagonists. The lipomobilization due to infusion of catecholamines (0.1, 0.5 or 5 micrograms/kg/min norepinephrine or 5 micrograms/kg/min epinephrine) was always suppressed by bupranolol or the combination of selective beta-antagonists. Thus dog adipocytes express functional beta 3-ARs. Their stimulation induces lipid mobilization. The lipomobilization of exogenously administered catecholamines is due only to the recruitment of beta 1- or beta 2-ARs. However, endogenous catecholamines released after sympathetic nervous system activation could stimulate beta 3-ARs in adipocytes only if a high level of sympathetic nervous system activity is realized.

Adipose Tissue↗
PubMedDate not supplied

Abnormal substrate metabolism and nutritional strategies in cancer management.

Impairment of the nutritional state plays a major role in the morbidity and mortality of cancer patients. However, the opportunity of providing artificial nutritional support to these patients is still debated, because of the concern that energy substrates administered to replete the host may concomitantly stimulate tumor growth. A correct nutritional approach to cancer patients should thus be based on a thorough knowledge of both host and tumor metabolic needs and host-tumor metabolic interactions. Specific modifications of plasma levels of glucogenic, aromatic, sulfur-containing and branched-chain amino acids have been demonstrated in cancer patients, indicating a specific influence of the tumor on amino acid metabolism. Little is known about protein metabolism in neoplastic tissue. Interference with tumor growth has been attempted by deprivation of single amino acids with controversial results. Increased gluconeogenesis and insulin resistance are responsible for the two main abnormalities in carbohydrate metabolism in cancer patients, namely increased glucose turnover and impaired glucose tissue disposal. Lipid metabolism is also affected by the neoplasm: soluble factors such as "lipid-mobilizing factor" lead to increased fat mobilization from adipose tissue; plasma elimination of exogenous triglycerides has also been found to be reduced probably because of a tumor-related decrease in lipoprotein lipase activity. The differences in glucose and fat utilization between tumor and host should be considered in the nutritional approach to cancer patients. Data in this respect are controversial and have been obtained only in experimental animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Carbohydrate Metabolism↗
PubMed1997

Modification of feed intake response to a beta 2-agonist by bovine somatotropin in lactating or dry dairy cows.

The aim of this experiment was to show whether growth hormone could increase the effect of the beta 2-adrenergic agonist clenbuterol on feed intake. Two groups of Holstein cows [lactating (n = 4) and dry (n = 4)] were used to rule out the possible effects of increased energy requirements on feed intake. Treatments were administered according to a crossover experimental design with two 13-d periods and an 8-d readjustment interval. Treatments consisted of daily injections of 40 mg of bST or a placebo. Moreover, clenbuterol (3.16 micrograms/kg of BW) or saline challenges were infused intravenously for 4 h either on d 8 or on d 11 of each period. The cows were offered a dehydrated total mixed diet for ad libitum intake for 4 h twice daily. For both groups of cows, clenbuterol reduced DMI on the experimental day only, and bST intensified the effects of clenbuterol on DMI, causing a sharper decrease in DMI over 2 d. This enhancement of clenbuterol activity modified certain metabolic parameters including higher lipid mobilization during infusion and higher glycogenolysis. For dry cows, the initial rate of eating was reduced under bST treatment alone. During early lactation, bST, either by itself or through increased beta 2-adrenergic stimulation may restrict the development of intake by dairy cows over a few weeks.

Adrenergic beta-Agonists↗
PubMed2005

Brain-adipose tissue cross talk.

While investigating the reversible seasonal obesity of Siberian hamsters, direct sympathetic nervous system (SNS) postganglionic innervation of white adipose tissue (WAT) has been demonstrated using anterograde and retrograde tract tracers. The primary function of this innervation is lipid mobilization. The brain SNS outflow to WAT has been defined using the pseudorabies virus (PRV), a retrograde transneuronal tract tracer. These PRV-labelled SNS outflow neurons are extensively co-localized with melanocortin-4 receptor mRNA, which, combined with functional data, suggests their involvement in lipolysis. The SNS innervation of WAT also regulates fat cell number, as noradrenaline inhibits and WAT denervation stimulates fat cell proliferation in vitro and in vivo respectively. The sensory innervation of WAT has been demonstrated by retrograde tract tracing, electrophysiological recording and labelling of the sensory-associated neuropeptide calcitonin gene-related peptide in WAT. Local injections of the sensory nerve neurotoxin capsaicin into WAT selectively destroy this innervation. Just as surgical removal of WAT pads triggers compensatory increases in lipid accretion by non-excised WAT depots, capsaicin-induced sensory denervation triggers increases in lipid accretion of non-capsaicin-injected WAT depots, suggesting that these nerves convey information about body fat levels to the brain. Finally, parasympathetic nervous system innervation of WAT has been suggested, but the recent finding of no WAT immunoreactivity for the possible parasympathetic marker vesicular acetylcholine transporter (VAChT) argues against this claim. Collectively, these data suggest several roles for efferent and afferent neural innervation of WAT in body fat regulation.

Adipose Tissue↗
PubMed1969

Hormonal regulation of lipolysis and phosphorylase activity in human fat cells.

Prostaglandin E(1) (PGE(1)) at a concentration of 1 ng/ml antagonized theophylline, and norepinephrine induced release of glycerol and free fatty acids (FFA) in human fat cell preparations. Insulin at higher doses also inhibited theophylline-stimulated lipolysis. The N(6)-2-0'dibutyryl derivative of cyclic adenosine monophosphate (DCAMP) stimulated lipolysis. Prostaglandin E(1) did not significantly inhibit the lipid mobilizing effects of DCAMP. Changes in glycogen phosphorylase activity after treatment with theophylline, norepinephrine, DCAMP, and PGE(1) paralleled those of lipolysis. These results suggest that in man as in experimental animals lipolysis and phosphorylase activity are regulated through processes involving cyclic AMP and that PGE(1) appears to exert its antilipolytic effect in human fat cells, as in rat fat cells, by interfering at the level of adenyl cyclase with the accumulation of cyclic AMP.

Adenylyl Cyclases↗
PubMed2006

Acute and chronic leptin reduces food intake and body weight in goldfish (Carassius auratus).

The purpose of the present study was to elucidate the possible role of leptin in food intake and body weight regulation in goldfish. We examined the effects of i.c.v. or i.p. acute leptin administration on food intake in food-deprived goldfish at different time intervals post-injection (0-2, 2-8 and 0-8 h). Food intake was reduced by i.p. administered leptin (1 microg) at 8 h post-injection, without statistically significant differences after i.c.v. treatment. The present study shows for the first time in a teleost that chronic (10 days) leptin treatment (i.p.) reduces food intake, body weight gain, specific growth rate and food efficiency ratio. Moreover, lipid and carbohydrate metabolism seems to be regulated by leptin in fish. Chronic leptin treatment increased lipid mobilization and carbohydrate storage as hepatic and muscle glycogen. Finally, leptin could mediate its actions on energy homeostasis in fish, at least in part, through interactions with hypothalamic catecholamines, since chronic leptin treatment reduced both hypothalamic noradrenergic and dopaminergic turnover without significant modifications in hypothalamic serotoninergic and neuropeptide Y (NPY) systems. In summary, our results suggest that leptin can regulate feeding behaviour and body weight homeostasis in fish.

Animals↗
PubMed1989

The effect of tumor necrosis factor alpha on the activity of lipoprotein lipase in adipose tissue.

TNF alpha may play a critical role in many physiologic and pathophysiologic responses. It shows a bifunctional regulatory nature of both inhibiting tumor cell proliferation and enhancing growth and differentiation of other cells. TNF alpha acts as a mediator, binding to specific high affinity receptors to elicit biological responses. TNF alpha may be an essential local and systemic mediator in the pathogenesis of cachexia. By inhibiting the activity of lipogenic enzymes, it affects lipid mobilization from adipose tissue and adipocyte differentiation. The ability of TNF alpha to inhibit anabolic processes in adipocytes and preadipocytes is not unique and has been displayed, though to a lesser degree, by other cytokines such as LT, IFN-gamma, and IL-1. In infected animals, the effect of TNF alpha on LPL of inhibiting anabolic processes and enhancing secretion of FFA by adipocytes, may be important in providing additional energy needed by the immune system to combat invasion. However, the relationship between the suppression of the anabolic processes and the cytotoxicity is uncertain and prolonged action may lead to wasting. The evidence suggests that in the adipocyte, TNF alpha is the unique molecule that suppresses LPL through the selective inhibition of mRNA production. As a consequence of the decrease in the enzyme amounts, there is a reduction in TG-uptake and lipid deposition contributing to cachexia. Neutralizing the action of TNF alpha may reverse the cachectic processes and potentially improve the condition. Further research into the induction, synthesis and regulation of TNF alpha production is necessary. Modern molecular biology techniques should serve as useful models in understanding the regulation of TNF alpha functions in response to stimuli. Development of faster and more sensitive detection methods would improve the measurement of the low concentrations of cytokines.

Adipose Tissue↗
PubMedDate not supplied

The pig as a model for the study of obesity and of control of food intake: a review.

The use of the pig for studies of food intake and obesity is reviewed. Effects of ambient temperature and taste on food intake as well as satiety factors impicating both neural and hormonal mechanisms originating in the gastrointestinal tract are considered; the integration of information in the central nervous system for both internal and external sources is hypothesized. Special concerns of food intake controls in the neonate are discussed, including effects of neonate sweet preference on food intake, gastrointestinal satiety factors, and hypoglycemia as a stimulus for food ingestion.For obesity studies, pigs offer several advantages, including their general physiological similarity to humans, similar fat cell size, and body fat distribution. Lipogenesis, lipolysis, and lipid mobilization are under intensive study in swine and the information obtained may have important application in studies of human obesity. The voluminous literature on metabolic differences between genetically lean versus obese populations of pigs suggests possibilities for application in humans. Greater characterization of differences and similarities between pigs and humans in important metabolic parameters related to regulation of food intake and obesity should facilitate better understanding and control of human obesity.

Adipose Tissue↗
PubMed2005

Effect of body fatness and glucogenic supplement on lipid and protein mobilization and plasma leptin in dairy cows.

Twenty-four multiparous Ayrshire cows were used in an experiment to test the effect of body fatness and glucogenic supplement, fed during the transition period, on lipid and protein mobilization and plasma hormone concentrations. Eight weeks before their expected calving date, the cows were divided into blocks of 4. Two cows with the highest body condition score within each block were then allocated to a test (T) group and the other 2 cows to a control (C) group. To scale up the differences between fatter and thinner cows, the estimated energy allowance was 40% higher in group T than in group C between d 56 and 21 prepartum. For the final 3 wk before calving, all the cows were fed according to energy recommendations for pregnant cows. Within C and T groups and blocks, cows were randomly assigned into groups with (G1) or without (G0) glucogenic supplement. Division to G0 and G1 groups was made 2 wk before the expected calving and continued for 56 d postpartum. After calving, all the cows received grass silage ad libitum and a common daily concentrate allowance. No significant differences were detected in feed intake and milk yield between C and T. The T groups showed an earlier rise of nonesterified fatty acids as calving approached and had higher plasma nonesterified fatty acids during the final week of pregnancy and lactation wk 1 to 3. At the same time, adipose tissue samples from fatter cows tended to show higher in vitro lipolytic responses to added norepinephrine, as monitored by glycerol release. Protein mobilization was elevated during the final week of pregnancy and tended to be more increased in fatter cows. Glucogenic supplement did not decrease lipid or protein mobilization. Fatter cows had higher plasma leptin concentration prepartum, showed a more pronounced decrease in leptin concentration near calving, and had higher plasma leptin concentration after calving. In conclusion, fatter cows initiated more extensive mobilization of body fat before calving and this continued during the first lactation weeks. Plasma leptin concentration in early-lactation cows was associated with body fatness and not with estimated energy balance.

Adipose Tissue↗
PubMed1987

Primary sequence analysis by fast atom bombardment mass spectrometry of a peptide with adipokinetic activity from the corpora cardiaca of the cricket Gryllus bimaculatus.

The octapeptide AKH-G, isolated from the cricket Gryllus bimaculatus, stimulates lipid mobilization in both the cricket itself and in migratory locusts. The structure of AKH-G has been assigned by fast atom bombardment mass spectrometry (FABMS) as pGlu-Val-Asn-Phe-Ser-Thr-Gly-Trp-NH2, and it is most closely related to AKH II-S from Schistocerca species, which has a Leu2 unit. Synthetic AKH-G, prepared by solid phase techniques, had the same bioactivity as the natural substance. FABMS measurements, including high-resolution and metastable studies, were made employing 400-900 pmole of sample.

Amino Acid Sequence↗
PubMed1987

Effects of tumor bearing and removal on blood levels of lipids, lipolytic activity, and glycerol and on carcass weight in the rat.

In this animal model we investigated the effects of sarcoma bearing and complete or incomplete tumor excision on blood levels of lipids, lipolytic activity, and glycerol and on carcass weight. We also sought causes that could account for the apparent increase in lipid mobilization. Tumor-bearing (TB) rats had depleted retroperitoneal fat stores, elevated blood triglycerides and cholesterol, and normal thyroid, hepatic, and renal function during tumor bearing. Catecholamine, growth hormone, and glucagon levels were not different between TB and nontumor-bearing (NTB) groups. Serum lipolytic activity and glycerol levels, which were elevated during tumor bearing, returned to NTB levels after complete tumor excision, along with restoration of retroperitoneal fat depots and carcass weight. The elevated serum lipolytic activity of animals that had tumors only incompletely excised rose significantly higher after the tumor regrew; this was accompanied by a failure to regain carcass weight. Previous work has shown that elevated lipolytic activity can also be demonstrated in culture media conditioned by growth of certain animal or human tumor cell lines in cell culture, free of host influences. This suggests that the actual tumor cell and not the host may be at least partly responsible for the lipid derangements seen in this model.

Animals↗
PubMed1993

Components of postprandial thermogenesis in relation to meal frequency in humans.

Experiments on dogs have shown that the size of the meal has no effect on the early cephalic postprandial thermogenesis, and that four small meals are more thermogenic than a larger meal with the same total caloric content as the four meals. A study was repeated on human subjects who were fed during alternating weeks either one large meal (653 kcal (1 kcal = 4.1855 kJ)) or four small meals (163 kcal) at 40-min intervals. Oxygen consumption and respiratory exchange ratio determinations indicated (i) larger overall increase in postprandial thermogenesis with the four meals than with one meal and (ii) an enhancement of glucose utilization with the large meal compared with greater lipid utilization with the four meals. On the basis of indirect evidence from previous investigations it is suggested that the enhanced thermogenesis observed in the four-meal experiment is due to lipid mobilization caused by repeated stimulation of the sympathetic nervous system with palatable food. Blood analysis indicated a reduced elevation of plasma glucose in the four-meal experiment. The variations of insulin and C-peptide exactly paralleled those observed for glucose. It is concluded that the increased frequency of feeding significantly reduces insulin secretion in subjects fed a relatively high carbohydrate meal. In addition to this beneficial effect, increasing the number of meals increased thermogenesis and fat utilization.

Adult↗
PubMed2001

Cancer anorexia and cachexia.

Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP-dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin-proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia.

Anorexia↗
PubMed2006

The chicken ovalbumin upstream promoter-transcription factors modulate genes and pathways involved in skeletal muscle cell metabolism.

The chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are "orphan" members of the nuclear hormone receptor (NR) superfamily. COUP-TFs are involved in organogenesis and neurogenesis. However, their role in skeletal muscle (and other major mass tissues) and metabolism remains obscure. Skeletal muscle accounts for approximately 40% of total body mass and energy expenditure. Moreover, this peripheral tissue is a primary site of glucose and fatty acid utilization. We utilize small interfering RNA (siRNA)-mediated attenuation of Coup-TfI and II (mRNA and protein) in a skeletal muscle cell culture model to understand the regulatory role of Coup-Tfs in this energy demanding tissue. This targeted NR repression resulted in the significant attenuation of genes that regulate lipid mobilization and utilization (including Pparalpha, Fabp3, and Cpt-1). This was coupled to reduced fatty acid beta-oxidation. Additionally we observed significant attenuation of Ucp1, a gene involved in energy expenditure. Concordantly, we observed a 5-fold increase in ATP levels in cells with siRNA-mediated repression of Coup-TfI and II. Furthermore, the expression of "classical" liver X receptor (LXR) target genes involved in reverse cholesterol transport (Abca1 and Abcg1) were both significantly repressed. Moreover, we observed that repression of the Coup-Tfs ablated the activation of Abca1, and Abcg1 mRNA expression by the selective LXR agonist, T0901317. In concordance, Coup-Tf-siRNA-transfected cells were refractory to Lxr-mediated reduction of total intracellular cholesterol levels in contrast to the negative control cells. In agreement Lxr-mediated activation of the Abca1 promoter in Coup-Tf-siRNA cells was attenuated. Collectively, these data suggest a pivotal role for Coup-Tfs in the regulation of lipid utilization/cholesterol homeostasis in skeletal muscle cells and the modulation of Lxr-dependent gene regulation.

ATP Binding Cassette Transporter 1↗
PubMed1990

Mitochondrial contact sites. Lipid composition and dynamics.

Two membrane fractions of intermediate density between inner and outer mitochondrial membranes were isolated by density gradient centrifugation from osmotically lysed mitochondria and mitoplasts of liver. These fractions were characterized by the presence of both monamine oxidase and cytochrome c oxidase activities and bound hexokinase. 1) The content of the fractions in proteins and lipids was assessed by biochemical determination. Thin-layer and gas-liquid chromatography showed that the two contact site-enriched fractions contain predominantly phosphatidylcholine (31%), phosphatidylethanolamine (27%, half-unsaturated), and cardiolipin (27%, fully unsaturated). 2) The dynamics of the fractions were assessed by fluorescence polarization techniques using 1,6-diphenyl-1,3,5-hexatriene as a probe and by fluorescence decay measurements. We have verified that differences in static anisotropy cannot be exclusively attributed to differences in fluorescence lifetimes. On the contrary, the results indicated an increased lipid mobility in "inner membrane contact sites," which is probably related to a lower cholesterol to phospholipid ratio, as well as a lower saturation of the fatty acyl chains when compared with "outer membrane contact sites." Taken all together, the spectroscopic measurements confirm the biochemical results, leading to the idea that the two populations of contact sites have different physicochemical properties, which are probably mainly determined by the membrane from which they are derived. They constitute microdomains enriched either in inner or outer mitochondrial membranes.

Animals↗
PubMed2001

Role of organochlorine compounds in the etiology of pancreatic cancer: a proposal to develop methodological standards.

Studies on the possible role of organochlorine compounds in the etiology of pancreatic and other cancers face a set of methodologic and logistic issues that stem from the lipophilic nature of most organochlorines, and from the fact that tumor-induced lipid mobilization, weight loss, and metabolic changes can be profound before diagnosis. The question thus arises: do the xenobiotic concentrations in blood and adipose tissue result, in part, from such pathophysiologic changes? To assess and control potential selection and information biases, a flexible framework is warranted. It could be based on indicators such as time elapsed between the first symptom of cancer and blood or fat sample extraction; signs, symptoms and clinical status at the time of extraction; cholesterol and triglycerides levels; other laboratory findings; tumor stage at diagnosis; diagnostic procedures; treatment type and timing; clinical complications; and survival. Before adopting qualitative criteria and quantitative standards, their impact upon causal estimators should be assessed empirically.

DDT↗