Biomedical subjects

Patrick Tso

Publications and source records attributed to Patrick Tso.

At least 19 recordsLinked to original sources

PubMed2006

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND: Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann's Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

Adult↗

PubMed2006

The regulation of alcohol intake by melanin-concentrating hormone in rats.

Given into the brain, melanin-concentrating hormone (MCH) increases alcohol consumption, but the mechanism and physiological relevance of this effect are unclear. We hypothesized that endogenous MCH will enhance alcohol drinking and that MCH increases alcohol's reinforcing properties. An MCH receptor 1 (MCHR1) antagonist, or saline was administered centrally alone, or preceding MCH or saline to rats trained to drink 10% alcohol using sucrose fading. Blocking MCHR1 neither reduced alcohol intake (saline=0.4+/-0.1 g, 30 microg MCHR1 antagonist=0.4+/-0.1 g/kg alcohol), nor attenuated MCH-induced alcohol drinking (MCHR1 antagonist/saline=0.7+/-0.1 g/kg, MCHR1 antagonist/MCH=0.9+/-0.1 g/kg alcohol). Another cohort of rats was trained to lever press for alcohol on a progressive ratio schedule. MCH or saline was administered centrally and lever presses were measured. MCH had no effect prior to the break point, but increased total responding during the session (saline=87.2+/-32.0, MCH=315.4+/-61.0 presses). In conclusion, these data suggest that MCH augments alcohol drinking partly by enhancing the drug's reinforcing value. Further, endogenous MCH does not seem to regulate alcohol drinking, however because the antagonist failed to attenuate MCH-induced alcohol intake this conclusion is tentative.

Alcohol Drinking↗

PubMed2006

Mechanism of the induction of brain c-Fos-positive neurons by lipid absorption.

Many gastrointestinal meal-related signals are transmitted to the central nervous system via the vagus nerve and thereby control changes in meal size. The c-Fos-positive neuron has been used as a marker of neuronal activation after lipid meals to examine the contribution of a selective macronutrient on brain neurocircuit activity. In rats fed Intralipid, the c-Fos-positive neurons were highly stimulated in the nucleus of the solitary tract (NTS) and in the hypothalamus, including the paraventricular nucleus (PVN), arcuate nucleus of the hypothalamus (ARC), and ventromedial hypothalamus at 4 h lipid feeding. However, c-Fos-like immunoreactivity was markedly attenuated in these brain regions when chylomicron formation/secretion was blocked by Pluronic L-81. After lymph was diverted from the lymph cannulated animals, the rats had a lower number of c-Fos-positive cells in the NTS and ARC. In contrast, the rats had higher c-Fos-positive neurons in PVN. The present study also revealed that c-Fos-positive neurons induced by feeding of Intalipid were abolished by CCK type 1 receptor antagonist, Lorglumide. We conclude that the formation and/or secretion of chylomicron are critical steps for initiating neuronal activation in the brain.

Animals↗

PubMed2006

CD36 is important for chylomicron formation and secretion and may mediate cholesterol uptake in the proximal intestine.

BACKGROUND & AIMS: Studies are aimed to determine the role of CD36 in intestinal lipid absorption. METHODS: Knock-out (KO) and wild-type (WT) lymph fistula mice were used to study fatty acids (FA) and cholesterol uptake, and chylomicron formation and secretion. Uptake of FA and cholesterol was studied by using sucrose polybehenate and fecal dual isotope methods, respectively. RESULTS: The CD36 KO exhibited significant accumulation of dietary cholesterol in the intestinal lumen at the end of 6-hour lipid infusion and significant reduction of dietary cholesterol transport into the lymph. Fecal dual isotope studies, however, did not show any significant difference in cholesterol uptake, suggesting that given sufficient time, the KO intestine could compensate for the reduced cholesterol uptake observed in the acute lymph fistula studies. Recovery of dietary FA in the intestinal lumen was comparable between WT and KO, consistent with the sucrose polybehenate study. However, the KO mice accumulated more, albeit not significantly, dietary triacylglycerols in the intestine, followed by a significant reduction in lymphatic transport. The ratio of intestinal dietary triacylglycerols to FA was not higher in WT than KO, arguing against impaired lipid esterification. It is rather a deficiency in the formation and secretion of chylomicrons, as supported by the significantly less apolipoprotein B-48 and the smaller, albeit not significantly, lipoprotein particles secreted into the lymph of the KO. CONCLUSIONS: CD36 may play an important role in chylomicron formation and secretion and may also facilitate cholesterol uptake in the proximal intestine.

Animals↗

PubMed2006

The prolactin-deficient mouse has an unaltered metabolic phenotype.

Prolactin (PRL), best recognized for its lactogenic activity, is also involved in the regulation of metabolic homeostasis in both mammalian and nonmammalian species. Although several mouse models have been used to study the metabolic functions of PRL, a clear-cut consensus has not emerged given the limited and often conflicting data. To clarify the role of PRL in metabolic homeostasis in males and nonlactating females, we used the PRL-deficient mouse. Our objectives were to compare: 1) weight gain, 2) body composition, 3) serum lipid profile, 4) circulating leptin and adiponectin levels, and 5) glucose tolerance in PRL knockout, heterozygous, and wild-type mice maintained on standard chow, high-fat, or low-fat diets. In addition, we compared the lipolytic actions of PRL using adipose tissue explants from mice, rats, and humans. We are reporting that PRL deficiency does not affect the rate of weight gain, body composition, serum lipids, or adiponectin levels in either sex on any diet. Glucose tolerance was slightly impaired in very young PRL knockout male pups but not in adults or in females at any age. Leptin was elevated in male, but not female, PRL knockout mice maintained on a low-fat diet. PRL did not affect lipolysis in adipose tissue explants from mice but significantly inhibited glycerol release from both rat and human adipose explants in a dose-dependent manner. We conclude that PRL deficiency has negligible gross metabolic effects in mice.

Adiponectin↗

PubMed2006

FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.

FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the alpha1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress beta-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with (3)H(2)O is suppressed by approximately 70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.

Adenoviridae↗

PubMed2006

Tissue uptake of DDT is independent of chylomicron metabolism.

AIM: To determine whether DDT uptake from chylomicrons (CM) into tissues is coincident with CM core lipid uptake. METHOD: CM were collected from mesenteric lymph duct cannulated, male Sprague-Dawley rats administered olive oil containing 3H-Cholesterol (converted to cholesterol ester (CE) during absorption through the intestine) and 14C-DDT by oral gavage. The CM were suspended in normal saline and 400 microL (containing 0.11 microCi/mL 14C-DDT and 0.15 microCi/mL 3H-CE) was administered via the jugular vein to the recipient rats. The blood was sampled periodically over 30 min from the carotid artery and at the end of the experiment the adrenal glands, brain, fat, heart, liver and spleen were collected. The concentration of 14C-DDT and 3H-CE in whole blood samples and tissue samples was then determined. RESULTS: DDT was removed from the whole blood and, therefore, CM at a significantly faster rate than CE (alpha = 0.05). The tissue distribution of DDT was also different from that of CE, and DDT was particularly concentrated in the retriperitoneal fat and brain. For DDT, the values for VBdB and Cl were significantly higher compared with those determined for CE. CONCLUSION: DDT is absorbed predominantly via the intestinal lymphatic system in association with CM and accumulates in fatty tissues. This study furthers the understanding of the process of DDT uptake from CM into tissues and demonstrates that the uptake of DDT into tissues is faster than and independent of the uptake of CM core lipid (using CE as a marker). DDT was particularly concentrated in fatty tissues, accounting for its relatively high VBDB.

Animals↗

PubMed2006

An acute and coincident increase in FABP expression and lymphatic lipid and drug transport occurs during intestinal infusion of lipid-based drug formulations to rats.

PURPOSE: To determine a) whether administration of lipid-based formulations can acutely up-regulate the intestinal expression of I-FABP and L-FABP and b) whether this occurs coincidentally with an increase in intestinal lymphatic lipid and drug transport. METHODS: The expression of I-FABP and L-FABP mRNA (using q-PCR) and protein (using immunohistochemistry and Western blotting) in enterocytes was compared with data describing transport of lipid and drug into intestinal lymph following infusion of a set of lipid-based formulations. RESULTS: Administration of relatively small amounts of oleic acid (5-20 mg/h) over a 5 h period to rats acutely up-regulated the expression, and altered the intracellular distribution of, I-FABP and L-FABP in the enterocytes of the small intestinal epithelia. The increase in expression of I-FABP and L-FABP correlated well with previous data describing the transport of lipid and drug into intestinal lymph following infusion of the same formulations. CONCLUSION: The expression and intracellular distribution of I-FABP and L-FABP are acutely influenced by lipid infusion over a time period relevant to feeding or the administration of pharmaceutical lipidic formulations, and these changes occur coincidentally with increased drug transport into the lymphatics.

Animals↗

PubMed2005

Apolipoprotein A-IV interacts synergistically with melanocortins to reduce food intake.

Apolipoprotein (apo) A-IV is an anorexigenic gastrointestinal peptide that is also synthesized in the hypothalamus. The goal of these experiments was to determine whether apo A-IV interacts with the central melanocortin (MC) system in the control of feeding. The third ventricular (i3vt) administration of a subthreshold dose of apo A-IV (0.5 microg) potentiated i3vt MC-induced (metallothionein-II, 0.03 nmol) suppression of 30-min feeding in Long-Evans rats. A subthreshold dose of the MC antagonist (SHU9119, 0.1 nmol, i3vt) completely attenuated the anorectic effect of i3vt apo A-IV (1.5 microg). The i3vt apo A-IV significantly elevated the expression of c-Fos in neurons of the paraventricular nucleus of the hypothalamus, but not in the arcuate nucleus or median eminence. In addition, c-Fos expression was not colocalized with proopiomelanocortin-positive neurons. These data support a synergistic interaction between apo A-IV and melanocortins that reduces food intake by acting downstream of the arcuate.

Animals↗

PubMed2005

Specific sequences in the N and C termini of apolipoprotein A-IV modulate its conformation and lipid association.

Apolipoprotein (apoA-IV) is a 376-residue exchangeable apolipoprotein that may play a number of important roles in lipid metabolism, including chylomicron assembly, reverse cholesterol transport, and appetite regulation. In vivo, apoA-IV exists in both lipid-poor and lipid-associated forms, and the balance between these states may determine its function. We examined the structural elements that modulate apoA-IV lipid binding by producing a series of deletion mutants and determining their ability to interact with phospholipid liposomes. We found that the deletion of residues 333-343 strongly increased the lipid association rate versus native apoA-IV. Additional mutagenesis revealed that two phenylalanine residues at positions 334 and 335 mediated this lipid binding inhibitory effect. We also observed that residues 11-20 in the N terminus were required for the enhanced lipid affinity induced by deletion of the C-terminal sequence. We propose a structural model in which these sequences can modulate the conformation and lipid affinity of apoA-IV.

Amino Acid Sequence↗

PubMed2005

The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension.

BACKGROUND: Sitosterolemia is a recessively inherited disorder in humans that is associated with premature atherosclerotic disease. Mutations in ABCG5 or ABCG8, comprising the sitosterolemia locus, STSL, are now known to cause this disease. Three in-bred strains of rats, WKY, SHR and SHRSP, are known to be sitosterolemic, hypertensive and they carry a missense 'mutation' in a conserved residue of Abcg5, Gly583Cys. Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension. METHODS: To investigate whether the missense change in Abcg5 is responsible for the sitosterolemia we performed a segregation analysis in 103 F2 rats from a SHR x SD cross. Additionally, we measured tail-cuff blood pressure and measured intestinal lipid transport to identify possible mechanisms whereby this mutation causes sitosterolemia. RESULTS: Segregation analysis showed that the inheritance of the Gly583Cys mutation Abcg5 segregated with elevated plant sterols and this pattern was recessive, proving that this genetic change is responsible for the sitosterolemia in these rat strains. Tail-cuff monitoring of blood pressure in conscious animals showed no significant differences between wild-type, heterozygous and homozygous mutant F2 rats, suggesting that this alteration may not be a significant determinant of hypertension in these rats on a chow diet. CONCLUSION: This study shows that the previously identified Gly583Cys change in Abcg5 in three hypertension-susceptible rats is responsible for the sitosterolemia, but may not be a major determinant of blood pressure in these rats.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity.

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-alpha. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-alpha agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

Animals↗

PubMed2005

CD36 deficiency impairs intestinal lipid secretion and clearance of chylomicrons from the blood.

CD36 mediates the transfer of fatty acids (FAs) across the plasma membranes of muscle and adipose cells, thus playing an important role in regulating peripheral FA metabolism in vivo. In the proximal intestine, CD36 is localized in abundant quantities on the apical surface of epithelial cells, a pattern similar to that of other proteins implicated in the uptake of dietary FAs. To define the role of CD36 in the intestine, we examined FA utilization and lipoprotein secretion by WT and CD36-null mice in response to acute and chronic fat feeding. CD36-null mice given a fat bolus by gavage or fed a high-fat diet accumulated neutral lipid in the proximal intestine, which indicated abnormal lipid processing. Using a model in which mice were equipped with lymph fistulae, we obtained evidence of defective lipoprotein secretion by directly measuring lipid output. The secretion defect appeared to reflect an impaired ability of CD36-null enterocytes to efficiently synthesize triacylglycerols from dietary FAs in the endoplasmic reticulum. In the plasma of intact mice, the reduced intestinal lipid secretion was masked by slow clearance of intestine-derived lipoproteins. The impaired clearance occurred despite normal lipoprotein lipase activity and likely reflected feedback inhibition of the lipase by FAs due to their defective removal from the plasma. We conclude that CD36 is important for both secretion and clearance of intestinal lipoproteins. CD36 deficiency results in hypertriglyceridemia both in the postprandial and fasting states and in humans may constitute a risk factor for diet-induced type 2 diabetes and cardiovascular disease.

Animals↗

PubMed2005

GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats.

Glucagon-like peptide 1 (GLP-1) is a gastrointestinal hormone secreted in response to meal ingestion by enteroendocrine L cells located predominantly in the lower small intestine and large intestine. GLP-1 inhibits the secretion and motility of the upper gut and has been suggested to play a role in the "ileal brake." In this study, we investigated the effect of recombinant GLP-1-(7-36) amide (rGLP-1) on lipid absorption in the small intestine in intestinal lymph duct-cannulated rats. In addition, the effects of rGLP-1 on intestinal production of apolipoprotein (apo) B and apo A-IV, two apolipoproteins closely related to lipid absorption, were evaluated. rGLP-1 was infused through the jugular vein, and lipids were infused simultaneously through a duodenal cannula. Our results showed that infusion of rGLP-1 at 20 pmol.kg(-1).min(-1) caused a dramatic and prompt decrease in lymph flow from 2.22 +/- 0.15 (SE) ml/h at baseline (n = 6) to 1.24 +/- 0.06 ml/h at 2 h (P < 0.001). In contrast, a significant increase in lymph flow was observed in the saline (control) group: 2.19 +/- 0.20 and 3.48 +/- 0.09 ml/h at baseline and at 6 h of lipid infusion, respectively (P < 0.001). rGLP-1 also inhibited intestinal triolein absorption (P < 0.05) and lymphatic apo B and apo A-IV output (P < 0.05) but did not affect cholesterol absorption. In conclusion, rGLP-1 dramatically decreases intestinal lymph flow and reduces triglyceride absorption and apo B and apo A-IV production. These findings suggest a novel role for GLP-1 in lipid absorption.

Animals↗

PubMed2005

Treatment with a dietary fat substitute decreased Arochlor 1254 contamination in an obese diabetic male.

A case manifesting symptoms due to organochlorine toxicity was treated with the fat substitute olestra in his diet. Before treatment, the patient was obese, with severe type 2 diabetes mellitus and mixed hyperlipidemia, chloracne, frequent headaches, and numbness and paraesthesias of his trunk and lower limbs. Earlier attempts at weight loss had been unsuccessful due to worsening of his symptoms. After inclusion of olestra in his diet for 2 years, weight loss was successful without aggravation of his symptoms, and the patient reverted to normoglycemia and normolipidemia. Olestra may have assisted weight loss and amelioration of his diabetes by increasing fecal elimination of organochlorines, rather than by preventing the partitioning of these pollutants into tissues, where they have been reported to exert antimetabolic effects on substrate oxidation.

Adipose Tissue↗

PubMed2005

Bacterial expression and characterization of rat apolipoprotein E.

Apolipoprotein (apo) E is a protein involved in both lipid metabolism and neuroprotection. Recently, it has been suggested that apoE may play a role in the regulation of food intake and body weight in rodents. However, rodent plasma apoE is difficult to purify in reasonable amounts due to numerous time-consuming steps. To circumvent this, we created a bacterial expression system for the efficient production of large amounts of rat apoE. We inserted rat apoE DNA into the pET30 expression vector and overexpressed the proteins in Escherichia coli strain BL21 (DE3). A histidine tag present at the N-terminus allowed for easy purification of the recombinant protein. The tag was removed with an IgA protease (Igase) from Neisseria gonorrhoeae leaving the mature form of the protein. The use of Igase was important as several more common proteases routinely cleave apolipoproteins at undesired sites. The recombinant protein was then compared both structurally and functionally to rat plasma apoE. This expression system will be highly useful for probing the ability of rat apoE to mediate food intake in rats.

Animals↗

PubMed2005

The role of apolipoprotein AIV on the control of food intake.

Apolipoprotein AIV (apo AIV) is a protein synthesized by the human intestine. The synthesis and secretion of apo AIV are stimulated by fat absorption. In 1992, Fujimoto et al. [1] first demonstrated that apo AIV is a satiety signal secreted by the small intestine following the ingestion of a lipid meal. This initial observation was followed by a number of studies supporting apo AIV's role as a satiety signal. This review article discusses the regulation of synthesis of apo AIV in the small intestine as well as the hypothalamus. In addition, the evidence that apo AIV is a satiety factor and its role of apo AIV in diet induced obesity will be discussed. We hope this review will serve as a catalyst to promote apo AIV research in the future. With most of the required reagents available, e.g., the apo AIV knockout and transgenic animals and apo AIV antibodies, the next few years should bring considerable new information on the function of apo AIV.

Animals↗

PubMed2004

Consumption of a high-fat diet alters the homeostatic regulation of energy balance.

Humans in many countries are currently experiencing what has been called an epidemic of obesity. That is, the average body weight (and amount of fat stored in the body) is increasing over years, carrying with it a multitude of associated medical, psychological, and economic problems. While there is no shortage of possible causes of this epidemic, increased availability and consumption of high-fat (HF), calorically dense and generally quite palatable food is often touted as a likely culprit. In order to better assess the impact of consuming a diet with those qualities, we have developed a well-controlled animal model in which the effects of chronic consumption of a high-fat diet can be dissociated from those of becoming obese per se. Long-Evans rats are fed one of two semipurified pelleted diets, a HF diet that contains 20% fat by weight and a low-fat (LF) diet that contains 4% fat by weight. Pair-fed animals consume the HF diet but are limited to the daily caloric intake of LF rats. Another group receives pelleted chow. Relative to animals consuming diets low in fat, HF animals weigh more, have more carcass fat, are hyperinsulinemic and hyperleptinemic, and are insulin resistant. HF-fed animals, independent of whether they become obese or not, also have central insulin and MTII insensitivity. Finally, HF rats have a down-regulated hypothalamic apo A-IV system that could contribute to their hyperphagia.

Animals↗