Jack Magrisso - Academia.edu (original) (raw)

Papers by Jack Magrisso

Journal of Medicinal Chemistry, Aug 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Journal of Medicinal Chemistry, Mar 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Neuroscience, May 1, 2012

Data from our lab indicate that the orexin system is involved in the regulation of both condition... more Data from our lab indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. Here, we tested the hypothesis that PVT orexin signaling mediates mesolimbic dopamine and reward-based feeding. To do this we used a behavioral pharmacological approach in tandem with central genetic manipulation of the orexin-1 receptor in the PVT. Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward-based feeding.

Journal of Medicinal Chemistry, Jul 1, 1998

Page 1144. The last sentence of footnote a of Table 5 should read as follows: σ 2 Binding assays ... more Page 1144. The last sentence of footnote a of Table 5 should read as follows: σ 2 Binding assays were determined in guinea pig brain using [ 3 H]DTG in the presence of an excess of (+)-NANM to mask σ 1 binding sites.

Journal of Medicinal Chemistry, Mar 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Journal of applied physiology (Bethesda, Md. : 1985), Sep 21, 2016

Exercise is an effective therapy against the metabolic syndrome. Yet, the molecular pathways unde... more Exercise is an effective therapy against the metabolic syndrome. Yet, the molecular pathways underlying the advantageous effects of exercise are elusive. Glucagon receptor signaling is essential for exercise benefits and recent evidence indicates that a downstream effector of glucagon, fibroblast growth factor 21 (FGF21), is implicated in this response. Therefore, we tested the hypothesis that FGF21 action is necessary in mediating metabolic effects of exercise. We utilized acute exhaustive treadmill exercise in Wistar rats to identify a putative, concomitant, increase in plasma glucagon and FGF21 with the increase in glucose and lactate following exercise. To test the necessity of FGF21 action in the exercise response, we exposed FGF21 congenitally-deficient mice (Fgf21(-/-)) and their Wild-type (Wt) littermates to chronic high-fat (HF) feeding and inoperable (sedentary) or operable (exercise) voluntary running wheels. Physiological tests were performed to assess the role of FGF21 ...

Molecular Metabolism, 2015

Human gene therapy methods, 2013

Helper-dependent adenoviral vectors (HD Ad) hold extreme promise for gene therapy of human diseas... more Helper-dependent adenoviral vectors (HD Ad) hold extreme promise for gene therapy of human diseases. All viral genes are deleted in HD Ad vectors, and therefore, the presence of a helper virus is required for their production. Current methods to minimize helper contamination in large-scale preparations rely on the use of the Cre/loxP system. The inclusion of loxP sites flanking the packaging signal results in its excision in the presence of Cre recombinase, preventing helper genome encapsidation. It is well established that the level of Cre recombinase activity is important in determining the degree of helper contamination. However, there is little information on other mechanisms that could also play an important role. We have generated several HD Ad vectors containing a rapalog-inducible system to regulate transgene expression, or LacZ under the control of the elongation factor 1 α promoter. Large-scale production of these vectors resulted in abundant helper contamination. Viral DN...

Laboratory investigation; a journal of technical methods and pathology, 1993

Recent evidence suggests that progressive stages of colorectal tumorigenesis can be defined by a ... more Recent evidence suggests that progressive stages of colorectal tumorigenesis can be defined by a sequence of genetic events characterized by deletion and expression of certain genes and appearance of several oncoproteins. Although the significance of these events is not entirely clear, oncoprotein expression may be directly involved in the tumorigenic mechanism. We examined the expression of two nuclear oncoproteins, JUN and FOS (Abbreviations used in this paper are lower case letters for oncogenes and upper case letters for oncoproteins), that have not been previously associated with development of colorectal cancer. This study involved detecting p39 c-JUN and p55 c-FOS, as well as two oncoproteins previously known to be expressed during colorectal tumorigenesis, p21 RAS and the tumor suppressor protein, p53. Expression was detected with immunohistochemical methods on formalin-fixed, paraffin-embedded sections of normal human colons, tubular adenomas, tubulovillous adenomas, and ad...

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2012

Although omega-3 (n À 3) fatty acids negatively regulate triglyceride biosynthesis, the mechanism... more Although omega-3 (n À 3) fatty acids negatively regulate triglyceride biosynthesis, the mechanisms mediating this effect are poorly understood, and emerging evidence suggests that stearoyl-CoA desaturase (Scd1) is required for de novo triglyceride biosynthesis. To investigate this mechanism, we determined the effects of perinatal n À 3 deficiency and postnatal repletion on rat liver Scd1 mRNA expression and activity indices (liver 16:1/16:0 and 18:1/18:0 ratios), and determined relationships with postprandial (non-fasting) plasma triglyceride levels. Rats were fed conventional diets with or without the n À 3 fatty acid precursor a-linolenic acid (ALA, 18:3n À 3) during perinatal development

Pharmacological Research, 2012

Psychiatric patients frequently exhibit long-chain n−3 (LCn−3) fatty acid deficits and elevated t... more Psychiatric patients frequently exhibit long-chain n−3 (LCn−3) fatty acid deficits and elevated triglyceride (TAG) production following chronic exposure to second generation antipsychotics (SGAs). Emerging evidence suggests that SGAs and LCn−3 fatty acids have opposing effects on stearoyl-CoA desaturase-1 (SCD1), which plays a pivotal role in TAG biosynthesis. Here we evaluated whether low LCn−3 fatty acid status would augment elevations in rat liver and plasma TAG concentrations following chronic treatment with the SGA risperidone (RSP), and evaluated relationships with hepatic SCD1 expression and activity indices. In rats maintained on the n−3 fatty acid-fortified (control) diet, chronic RSP treatment significantly increased liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios), and significantly increased liver, but not plasma, TAG concentrations. Rats maintained on the n−3 deficient diet exhibited significantly lower liver and erythrocyte LCn−3 fatty acid levels, and associated elevations in LCn−6/LCn−3 ratio. In n−3 deficient rats, RSP-induced elevations in liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios) and liver and plasma TAG concentrations were significantly greater than those observed in RSP-treated controls. Plasma glucose levels were not altered by diet or RSP, and body weight was lower in RSP-and VEH-treated n−3 deficient rats. These preclinical data support the hypothesis that low n−3 fatty acid status exacerbates RSP-induced hepatic steatosis by augmenting SCD1 expression and activity.

Peptides, 2011

The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs m... more The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs mediate leptin transport that is essential for its CNS actions, and both endothelial and astrocytic LRs may be involved. To test this, we generated endothelia specific LR knockout (ELKO) and astrocyte specific LR knockout (ALKO) mice. ELKO mice were derived from a cross of Tie2-cre recombinase mice with LR-floxed mice, whereas ALKO mice were generated by a cross of GFAP-cre with LR-floxed mice, yielding mutant transmembrane LRs without signaling functions in endothelial cells and astrocytes, respectively. The ELKO mutation did not affect leptin half-life in blood or apparent influx rate to the brain and spinal cord, though there was an increase of brain parenchymal uptake of leptin after in-situ brain perfusion. Similarly, the ALKO mutation did not affect blood-brain barrier permeation of leptin or its degradation in blood and brain. The results support our observation from cellular studies that membrane-bound truncated LRs are fully efficient in transporting leptin, and that basal levels of astrocytic LRs do not affect leptin transport across the endothelial monolayer. Nonetheless, the absence of leptin signaling at the BBB appears to enhance the availability of leptin to CNS parenchyma. The ELKO and ALKO mice provide new models to determine the dynamic regulation of leptin transport in metabolic and inflammatory disorders where cellular distribution of LRs is shifted.

Obesity Surgery, 2013

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat... more Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.

Nutrition Research, 2011

This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and s... more This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids.

Molecular Endocrinology, 2008

The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, red... more The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor ␣ (ER␣) and ␤ (ER␤), in 17␤-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ER␣ and ER␤ gene-deficient mice. Our study shows that whereas ER␣ mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that prefer-entially occurs in T cell receptor ␤ chain ؊/low double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor-B in CD25 ؊ CD4 ؊ CD8 ؊ double-negative thymocytes through an ER␣-dependent yet ER␤and GPR30-independent pathway. Differential inhibition of nuclear factor-B by ER␣ and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development. (Molecular Endocrinology 22: 636-648, 2008)

Journal of Medicinal Chemistry, 1998

Hormones and Behavior, 2012

Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. ... more Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a "Dessert Effect" protocol in which the intake of a palatable high fat diet "dessert" was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.

Diabetologia, 2011

Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) an... more Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function. Methods Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.

Journal of Medicinal Chemistry, Aug 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Journal of Medicinal Chemistry, Mar 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Neuroscience, May 1, 2012

Data from our lab indicate that the orexin system is involved in the regulation of both condition... more Data from our lab indicate that the orexin system is involved in the regulation of both conditioned and unconditioned responding for palatable foods. Anticipation of food rewards activates orexin receptor containing neurons within the paraventricular nucleus of the thalamus (PVT). The PVT regulates mesolimbic dopamine neurochemistry through direct connections with the nucleus accumbens and modulates the processing of cognitive-emotional information, suggesting that the PVT may represent a unique brain region with the capacity to mediate orexinergic effects on brain dopamine and behavior. Here, we tested the hypothesis that PVT orexin signaling mediates mesolimbic dopamine and reward-based feeding. To do this we used a behavioral pharmacological approach in tandem with central genetic manipulation of the orexin-1 receptor in the PVT. Data from these studies indicate that orexin-A action in the PVT increases dopamine levels in the nucleus accumbens. In addition, endogenous orexin signaling in the PVT mediates locomotor activity and hedonic feeding responses. Together these data highlight the PVT as a critical site capable of mediating orexin action on brain dopamine and reward-based feeding.

Journal of Medicinal Chemistry, Jul 1, 1998

Page 1144. The last sentence of footnote a of Table 5 should read as follows: σ 2 Binding assays ... more Page 1144. The last sentence of footnote a of Table 5 should read as follows: σ 2 Binding assays were determined in guinea pig brain using [ 3 H]DTG in the presence of an excess of (+)-NANM to mask σ 1 binding sites.

Journal of Medicinal Chemistry, Mar 1, 1998

We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-... more We report an expansion of the scope of our initial discovery that 5-keto-substituted 7-tertbutyl-2,3-dihydro-3,3-dimethylbenzofurans (DHDMBFs) are antiinflammatory and analgesic agents. Several other functional groups have been introduced at the 5 position: amides, amidines, ureas, guanidines, amines, heterocycles, heteroaromatics, and heteroaryl ethenyl substituents in the 5 position all provide active compounds. These compounds are dual cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitors. They inhibit both COX-1 and COX-2 with up to 33-fold selectivity for COX-2.

Journal of applied physiology (Bethesda, Md. : 1985), Sep 21, 2016

Exercise is an effective therapy against the metabolic syndrome. Yet, the molecular pathways unde... more Exercise is an effective therapy against the metabolic syndrome. Yet, the molecular pathways underlying the advantageous effects of exercise are elusive. Glucagon receptor signaling is essential for exercise benefits and recent evidence indicates that a downstream effector of glucagon, fibroblast growth factor 21 (FGF21), is implicated in this response. Therefore, we tested the hypothesis that FGF21 action is necessary in mediating metabolic effects of exercise. We utilized acute exhaustive treadmill exercise in Wistar rats to identify a putative, concomitant, increase in plasma glucagon and FGF21 with the increase in glucose and lactate following exercise. To test the necessity of FGF21 action in the exercise response, we exposed FGF21 congenitally-deficient mice (Fgf21(-/-)) and their Wild-type (Wt) littermates to chronic high-fat (HF) feeding and inoperable (sedentary) or operable (exercise) voluntary running wheels. Physiological tests were performed to assess the role of FGF21 ...

Molecular Metabolism, 2015

Human gene therapy methods, 2013

Helper-dependent adenoviral vectors (HD Ad) hold extreme promise for gene therapy of human diseas... more Helper-dependent adenoviral vectors (HD Ad) hold extreme promise for gene therapy of human diseases. All viral genes are deleted in HD Ad vectors, and therefore, the presence of a helper virus is required for their production. Current methods to minimize helper contamination in large-scale preparations rely on the use of the Cre/loxP system. The inclusion of loxP sites flanking the packaging signal results in its excision in the presence of Cre recombinase, preventing helper genome encapsidation. It is well established that the level of Cre recombinase activity is important in determining the degree of helper contamination. However, there is little information on other mechanisms that could also play an important role. We have generated several HD Ad vectors containing a rapalog-inducible system to regulate transgene expression, or LacZ under the control of the elongation factor 1 α promoter. Large-scale production of these vectors resulted in abundant helper contamination. Viral DN...

Laboratory investigation; a journal of technical methods and pathology, 1993

Recent evidence suggests that progressive stages of colorectal tumorigenesis can be defined by a ... more Recent evidence suggests that progressive stages of colorectal tumorigenesis can be defined by a sequence of genetic events characterized by deletion and expression of certain genes and appearance of several oncoproteins. Although the significance of these events is not entirely clear, oncoprotein expression may be directly involved in the tumorigenic mechanism. We examined the expression of two nuclear oncoproteins, JUN and FOS (Abbreviations used in this paper are lower case letters for oncogenes and upper case letters for oncoproteins), that have not been previously associated with development of colorectal cancer. This study involved detecting p39 c-JUN and p55 c-FOS, as well as two oncoproteins previously known to be expressed during colorectal tumorigenesis, p21 RAS and the tumor suppressor protein, p53. Expression was detected with immunohistochemical methods on formalin-fixed, paraffin-embedded sections of normal human colons, tubular adenomas, tubulovillous adenomas, and ad...

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2012

Although omega-3 (n À 3) fatty acids negatively regulate triglyceride biosynthesis, the mechanism... more Although omega-3 (n À 3) fatty acids negatively regulate triglyceride biosynthesis, the mechanisms mediating this effect are poorly understood, and emerging evidence suggests that stearoyl-CoA desaturase (Scd1) is required for de novo triglyceride biosynthesis. To investigate this mechanism, we determined the effects of perinatal n À 3 deficiency and postnatal repletion on rat liver Scd1 mRNA expression and activity indices (liver 16:1/16:0 and 18:1/18:0 ratios), and determined relationships with postprandial (non-fasting) plasma triglyceride levels. Rats were fed conventional diets with or without the n À 3 fatty acid precursor a-linolenic acid (ALA, 18:3n À 3) during perinatal development

Pharmacological Research, 2012

Psychiatric patients frequently exhibit long-chain n−3 (LCn−3) fatty acid deficits and elevated t... more Psychiatric patients frequently exhibit long-chain n−3 (LCn−3) fatty acid deficits and elevated triglyceride (TAG) production following chronic exposure to second generation antipsychotics (SGAs). Emerging evidence suggests that SGAs and LCn−3 fatty acids have opposing effects on stearoyl-CoA desaturase-1 (SCD1), which plays a pivotal role in TAG biosynthesis. Here we evaluated whether low LCn−3 fatty acid status would augment elevations in rat liver and plasma TAG concentrations following chronic treatment with the SGA risperidone (RSP), and evaluated relationships with hepatic SCD1 expression and activity indices. In rats maintained on the n−3 fatty acid-fortified (control) diet, chronic RSP treatment significantly increased liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios), and significantly increased liver, but not plasma, TAG concentrations. Rats maintained on the n−3 deficient diet exhibited significantly lower liver and erythrocyte LCn−3 fatty acid levels, and associated elevations in LCn−6/LCn−3 ratio. In n−3 deficient rats, RSP-induced elevations in liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios) and liver and plasma TAG concentrations were significantly greater than those observed in RSP-treated controls. Plasma glucose levels were not altered by diet or RSP, and body weight was lower in RSP-and VEH-treated n−3 deficient rats. These preclinical data support the hypothesis that low n−3 fatty acid status exacerbates RSP-induced hepatic steatosis by augmenting SCD1 expression and activity.

Peptides, 2011

The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs m... more The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs mediate leptin transport that is essential for its CNS actions, and both endothelial and astrocytic LRs may be involved. To test this, we generated endothelia specific LR knockout (ELKO) and astrocyte specific LR knockout (ALKO) mice. ELKO mice were derived from a cross of Tie2-cre recombinase mice with LR-floxed mice, whereas ALKO mice were generated by a cross of GFAP-cre with LR-floxed mice, yielding mutant transmembrane LRs without signaling functions in endothelial cells and astrocytes, respectively. The ELKO mutation did not affect leptin half-life in blood or apparent influx rate to the brain and spinal cord, though there was an increase of brain parenchymal uptake of leptin after in-situ brain perfusion. Similarly, the ALKO mutation did not affect blood-brain barrier permeation of leptin or its degradation in blood and brain. The results support our observation from cellular studies that membrane-bound truncated LRs are fully efficient in transporting leptin, and that basal levels of astrocytic LRs do not affect leptin transport across the endothelial monolayer. Nonetheless, the absence of leptin signaling at the BBB appears to enhance the availability of leptin to CNS parenchyma. The ELKO and ALKO mice provide new models to determine the dynamic regulation of leptin transport in metabolic and inflammatory disorders where cellular distribution of LRs is shifted.

Obesity Surgery, 2013

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat... more Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.

Nutrition Research, 2011

This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and s... more This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids.

Molecular Endocrinology, 2008

The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, red... more The mechanisms by which prolonged estrogen exposures, such as estrogen therapy and pregnancy, reduce thymus weight, cellularity, and CD4 and CD8 phenotype expression, have not been well defined. In this study, the roles played by the membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), and the intracellular estrogen receptors, estrogen receptor ␣ (ER␣) and ␤ (ER␤), in 17␤-estradiol (E2)-induced thymic atrophy were distinguished by construction and the side-by-side comparison of GPR30-deficient mice with ER␣ and ER␤ gene-deficient mice. Our study shows that whereas ER␣ mediated exclusively the early developmental blockage of thymocytes, GPR30 was indispensable for thymocyte apoptosis that prefer-entially occurs in T cell receptor ␤ chain ؊/low double-positive thymocytes. Additionally, G1, a specific GPR30 agonist, induces thymic atrophy and thymocyte apoptosis, but not developmental blockage. Finally, E2 treatment attenuates the activation of nuclear factor-B in CD25 ؊ CD4 ؊ CD8 ؊ double-negative thymocytes through an ER␣-dependent yet ER␤and GPR30-independent pathway. Differential inhibition of nuclear factor-B by ER␣ and GPR30 might underlie their disparate physiological effects on thymocytes. Our study distinguishes, for the first time, the respective contributions of nuclear and membrane E2 receptors in negative regulation of thymic development. (Molecular Endocrinology 22: 636-648, 2008)

Journal of Medicinal Chemistry, 1998

Hormones and Behavior, 2012

Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. ... more Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a "Dessert Effect" protocol in which the intake of a palatable high fat diet "dessert" was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.

Diabetologia, 2011

Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) an... more Aims/hypothesis We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function. Methods Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.