The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform
Paul Ernsberger - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Molecular Roles of Nutrients Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) 1,2,3
2013Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:ABSTRACT The genetically obese Koletsky Rat (SHROB, fa k) has a novel point mutation of the leptin receptor at amino acid �763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P � 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P � 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50 % in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism. J. Nutr. 128: 2299–2306, 1998
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The SHROB model of syndrome X: effects of excess dietary sucrose.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, David Bedol, David D. Kline, Jacob E. FriedmanAbstract:The obese SHR (SHROB strain, Koletsky Rat) is a spontaneous genetic knockout for the leptin receptor gene and shows many of the abnormalities that cluster in the human Syndrome X. The SHROB expresses genetic obesity, spontaneous hypertension, hyperinsulinemia, extreme insulin resistance, and hyperlipoproteinemia (Type IV).1,2 The syndrome of abnormalities in the SHROB results from a null mutation of the leptin receptor.3 In the 1970s inbred SHROB (Koletsky Rats) were sent to the National Institutes of Health (NIH), where they were outbred and crossed with Rats from various genetic backgrounds. These various substrains bearing the fak mutation were termed “corpulent” Rats. The so-called SHR/N-cp strain is similar to the parent SHROB line, but was crossed with a sepaRate SHR subline at NIH. The SHR/N-cp Rat is reported to develop severe diabetes, with random plasma glucose levels over 500 mg/dl, when fed a 54% sucrose diet.4 This same diet induced a fourfold increase in urinary protein excretion, implying an acceleRation of kidney disease.5 The parent SHROB strain is entirely normoglycemic on normal chow, although a 20-fold elevation in fasting plasma insulin implies profound insulin resistance. A further difference is that SHROB are markedly hypertensive, whereas SHR/N-cp show only mild hypertension. In the present study, we sought to determine whether the fak mutation on its original genetic background, the SHROB strain, promotes deleterious responses to a high sucrose diet, similar to the SHR/N-cp model bearing the same fak mutation. Excess dietary sucrose is thought to exacerbate the metabolic components of Syndrome X. We tested the effects of a 60% sucrose diet on SHROB.
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Molecular pathology in the obese spontaneous hypertensive Koletsky Rat: a model of syndrome X.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, Jacob E. FriedmanAbstract:: The SHROB Rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by sepaRate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxoni-dine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also amelioRated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
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Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese Rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive Rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substRate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
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Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
The Journal of nutrition, 1998Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:The genetically obese Koletsky Rat (SHROB, fa k ) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
Jacob E. Friedman - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Molecular Roles of Nutrients Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) 1,2,3
2013Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:ABSTRACT The genetically obese Koletsky Rat (SHROB, fa k) has a novel point mutation of the leptin receptor at amino acid �763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P � 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P � 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50 % in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism. J. Nutr. 128: 2299–2306, 1998
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Molecular pathology in the obese spontaneous hypertensive Koletsky Rat: a model of syndrome X.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, Jacob E. FriedmanAbstract:: The SHROB Rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by sepaRate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxoni-dine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also amelioRated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
-
The SHROB model of syndrome X: effects of excess dietary sucrose.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, David Bedol, David D. Kline, Jacob E. FriedmanAbstract:The obese SHR (SHROB strain, Koletsky Rat) is a spontaneous genetic knockout for the leptin receptor gene and shows many of the abnormalities that cluster in the human Syndrome X. The SHROB expresses genetic obesity, spontaneous hypertension, hyperinsulinemia, extreme insulin resistance, and hyperlipoproteinemia (Type IV).1,2 The syndrome of abnormalities in the SHROB results from a null mutation of the leptin receptor.3 In the 1970s inbred SHROB (Koletsky Rats) were sent to the National Institutes of Health (NIH), where they were outbred and crossed with Rats from various genetic backgrounds. These various substrains bearing the fak mutation were termed “corpulent” Rats. The so-called SHR/N-cp strain is similar to the parent SHROB line, but was crossed with a sepaRate SHR subline at NIH. The SHR/N-cp Rat is reported to develop severe diabetes, with random plasma glucose levels over 500 mg/dl, when fed a 54% sucrose diet.4 This same diet induced a fourfold increase in urinary protein excretion, implying an acceleRation of kidney disease.5 The parent SHROB strain is entirely normoglycemic on normal chow, although a 20-fold elevation in fasting plasma insulin implies profound insulin resistance. A further difference is that SHROB are markedly hypertensive, whereas SHR/N-cp show only mild hypertension. In the present study, we sought to determine whether the fak mutation on its original genetic background, the SHROB strain, promotes deleterious responses to a high sucrose diet, similar to the SHR/N-cp model bearing the same fak mutation. Excess dietary sucrose is thought to exacerbate the metabolic components of Syndrome X. We tested the effects of a 60% sucrose diet on SHROB.
-
Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese Rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive Rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substRate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
-
Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
The Journal of nutrition, 1998Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:The genetically obese Koletsky Rat (SHROB, fa k ) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
Richard J. Koletsky - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Molecular Roles of Nutrients Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) 1,2,3
2013Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:ABSTRACT The genetically obese Koletsky Rat (SHROB, fa k) has a novel point mutation of the leptin receptor at amino acid �763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P � 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P � 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50 % in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism. J. Nutr. 128: 2299–2306, 1998
-
The SHROB model of syndrome X: effects of excess dietary sucrose.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, David Bedol, David D. Kline, Jacob E. FriedmanAbstract:The obese SHR (SHROB strain, Koletsky Rat) is a spontaneous genetic knockout for the leptin receptor gene and shows many of the abnormalities that cluster in the human Syndrome X. The SHROB expresses genetic obesity, spontaneous hypertension, hyperinsulinemia, extreme insulin resistance, and hyperlipoproteinemia (Type IV).1,2 The syndrome of abnormalities in the SHROB results from a null mutation of the leptin receptor.3 In the 1970s inbred SHROB (Koletsky Rats) were sent to the National Institutes of Health (NIH), where they were outbred and crossed with Rats from various genetic backgrounds. These various substrains bearing the fak mutation were termed “corpulent” Rats. The so-called SHR/N-cp strain is similar to the parent SHROB line, but was crossed with a sepaRate SHR subline at NIH. The SHR/N-cp Rat is reported to develop severe diabetes, with random plasma glucose levels over 500 mg/dl, when fed a 54% sucrose diet.4 This same diet induced a fourfold increase in urinary protein excretion, implying an acceleRation of kidney disease.5 The parent SHROB strain is entirely normoglycemic on normal chow, although a 20-fold elevation in fasting plasma insulin implies profound insulin resistance. A further difference is that SHROB are markedly hypertensive, whereas SHR/N-cp show only mild hypertension. In the present study, we sought to determine whether the fak mutation on its original genetic background, the SHROB strain, promotes deleterious responses to a high sucrose diet, similar to the SHR/N-cp model bearing the same fak mutation. Excess dietary sucrose is thought to exacerbate the metabolic components of Syndrome X. We tested the effects of a 60% sucrose diet on SHROB.
-
Molecular pathology in the obese spontaneous hypertensive Koletsky Rat: a model of syndrome X.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, Jacob E. FriedmanAbstract:: The SHROB Rat is a unique strain with genetic obesity, hypertriglyceridemia, hyperinsulinemia, renal disease with proteinuria, and genetically determined hypertension, characteristics paralleling human Syndrome X. The obese phenotype results from a single homozygous recessive trait, designated faK, and is allelic with the Zucker fatty trait (fa), but of distinct origin. The faK mutation is a premature stop codon in the extracellular domain of the leptin receptor, resulting in a natural receptor knockout. The SHROB are glucose intolerant compared to heterozygous or wild-type SHR, but retain fasting euglycemia even on a high sucrose diet, suggesting that diabetes requires polygenic interaction with additional modifier genes. Insulin-stimulated phosphorylation of tyrosine residues on the insulin receptor and on the associated docking protein IRS-1 are reduced in skeletal muscle and liver compared to SHR, due mainly to diminished expression of insulin receptor and IRS-1 proteins. Despite multiple metabolic derangements and severe insulin resistance, hypertension is not exacerbated in SHROB compared to SHR. Thus, insulin resistance and hypertension are independent in this model. Increased activity of the sympathetic nervous system may be a common factor leading by sepaRate pathways to hypertension and to insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in SHROB. Moxoni-dine (8 mg/kg/day), a selective I1-imidazoline receptor agonist, not only reduced blood pressure but also amelioRated glucose intolerance. Moxonidine reduced fasting insulin by 47% and plasma free fatty acids by 30%. Moxonidine enhanced expression and insulin-stimulated phosphorylation of IRS-1 in skeletal muscle by 74 and 27%, respectively. Thus, central sympatholytic therapy not only counters hypertension but also insulin resistance, glucose tolerance, and hyperlipidemia in the SHROB model of Syndrome X.
-
Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese Rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive Rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substRate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
-
Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
The Journal of nutrition, 1998Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:The genetically obese Koletsky Rat (SHROB, fa k ) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
David Bedol - One of the best experts on this subject based on the ideXlab platform.
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Biochemical and Molecular Roles of Nutrients Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) 1,2,3
2013Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:ABSTRACT The genetically obese Koletsky Rat (SHROB, fa k) has a novel point mutation of the leptin receptor at amino acid �763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P � 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P � 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50 % in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism. J. Nutr. 128: 2299–2306, 1998
-
The SHROB model of syndrome X: effects of excess dietary sucrose.
Annals of the New York Academy of Sciences, 1999Co-Authors: Paul Ernsberger, Richard J. Koletsky, David Bedol, David D. Kline, Jacob E. FriedmanAbstract:The obese SHR (SHROB strain, Koletsky Rat) is a spontaneous genetic knockout for the leptin receptor gene and shows many of the abnormalities that cluster in the human Syndrome X. The SHROB expresses genetic obesity, spontaneous hypertension, hyperinsulinemia, extreme insulin resistance, and hyperlipoproteinemia (Type IV).1,2 The syndrome of abnormalities in the SHROB results from a null mutation of the leptin receptor.3 In the 1970s inbred SHROB (Koletsky Rats) were sent to the National Institutes of Health (NIH), where they were outbred and crossed with Rats from various genetic backgrounds. These various substrains bearing the fak mutation were termed “corpulent” Rats. The so-called SHR/N-cp strain is similar to the parent SHROB line, but was crossed with a sepaRate SHR subline at NIH. The SHR/N-cp Rat is reported to develop severe diabetes, with random plasma glucose levels over 500 mg/dl, when fed a 54% sucrose diet.4 This same diet induced a fourfold increase in urinary protein excretion, implying an acceleRation of kidney disease.5 The parent SHROB strain is entirely normoglycemic on normal chow, although a 20-fold elevation in fasting plasma insulin implies profound insulin resistance. A further difference is that SHROB are markedly hypertensive, whereas SHR/N-cp show only mild hypertension. In the present study, we sought to determine whether the fak mutation on its original genetic background, the SHROB strain, promotes deleterious responses to a high sucrose diet, similar to the SHR/N-cp model bearing the same fak mutation. Excess dietary sucrose is thought to exacerbate the metabolic components of Syndrome X. We tested the effects of a 60% sucrose diet on SHROB.
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Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese Rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive Rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substRate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
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Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
The Journal of nutrition, 1998Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:The genetically obese Koletsky Rat (SHROB, fa k ) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
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Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive Rats.
Blood Pressure, 1998Co-Authors: Jacob E. Friedman, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Paul ErnsbergerAbstract:Hypertension and insulin resistance are often part of a complex set of abnormalities including obesity, hyperlipidemia, and glucose intolerance, described as syndrome X. Besides a common genetic basis, insulin resistance and hypertension might be linked by excessive activity of the sympathetic nervous system. We studied the effects of chronic inhibition of sympathetic activity with the antihypertensive agent moxonidine on glucose metabolism in the genetically obese SHR Koletsky Rat (SHROB), a unique animal model which closely resembles human syndrome X, expressing genetic obesity, hypertension, and hyperlipidemia. Moxonidine, a selective I1-imidazoline receptor agonist, was administered to SHROB and SHR for 90 days in food at 8 mg/kg/day. Moxonidine not only lowered blood pressure, but also reduced fasting insulin levels by 49% in SHROB, and reduced plasma free fatty acids by 30%. In lean SHR, moxonidine treatment decreased circulating free fatty acids by 33% compared to controls. During oral glucose tole...
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Biochemical and Molecular Roles of Nutrients Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB) 1,2,3
2013Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:ABSTRACT The genetically obese Koletsky Rat (SHROB, fa k) has a novel point mutation of the leptin receptor at amino acid �763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P � 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P � 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50 % in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism. J. Nutr. 128: 2299–2306, 1998
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Mechanisms of Antihyperglycemic Effects of Moxonidine in the Obese Spontaneously Hypertensive Koletsky Rat (SHROB)
The Journal of pharmacology and experimental therapeutics, 1999Co-Authors: Paul Ernsberger, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Jacob E. FriedmanAbstract:Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese Rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive Rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor β subunit by 19% in SHROB but was without effect in SHR. The level of insulin receptor substRate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
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Phenotypic Consequences of a Nonsense Mutation in the Leptin Receptor Gene (fa k) in Obese Spontaneously Hypertensive Koletsky Rats (SHROB)
The Journal of nutrition, 1998Co-Authors: Tatsuya Ishizuka, Sha Liu, David Bedol, Richard J. Koletsky, Paul Ernsberger, Timothy M. Lehman, Jacob E. FriedmanAbstract:The genetically obese Koletsky Rat (SHROB, fa k ) has a novel point mutation of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all leptin receptor isoforms should be absent in this model. We examined the phenotypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermates. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb) form were expressed at comparable levels in SHROB and SHR in brain and throughout peripheral tissues. Adipose tissue mRNA for leptin was two to three times greater in SHROB compared to SHR (P < 0.01), while circulating leptin concentRation was 170 times greater than SHR littermates (P < 0.01), suggesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respectively); however, the CSF/plasma Ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were incubated in vitro with recombinant human leptin. Leptin directly suppressed insulin-mediated glucose transport by 50% in skeletal muscle from SHR but not in obese SHROB Rats lacking all forms of the leptin receptor. These results suggest that the natural leptin receptor knockout in the SHROB represents a unique Rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.
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Anti-hyperglycemic activity of moxonidine: metabolic and molecular effects in obese spontaneously hypertensive Rats.
Blood Pressure, 1998Co-Authors: Jacob E. Friedman, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Paul ErnsbergerAbstract:Hypertension and insulin resistance are often part of a complex set of abnormalities including obesity, hyperlipidemia, and glucose intolerance, described as syndrome X. Besides a common genetic basis, insulin resistance and hypertension might be linked by excessive activity of the sympathetic nervous system. We studied the effects of chronic inhibition of sympathetic activity with the antihypertensive agent moxonidine on glucose metabolism in the genetically obese SHR Koletsky Rat (SHROB), a unique animal model which closely resembles human syndrome X, expressing genetic obesity, hypertension, and hyperlipidemia. Moxonidine, a selective I1-imidazoline receptor agonist, was administered to SHROB and SHR for 90 days in food at 8 mg/kg/day. Moxonidine not only lowered blood pressure, but also reduced fasting insulin levels by 49% in SHROB, and reduced plasma free fatty acids by 30%. In lean SHR, moxonidine treatment decreased circulating free fatty acids by 33% compared to controls. During oral glucose tole...
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Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky Rat
The American journal of physiology, 1997Co-Authors: Jacob E. Friedman, Tatsuya Ishizuka, Sha Liu, Craig J. Farrell, David Bedol, Richard J. Koletsky, Hue-lee Cheng Kaung, Paul ErnsbergerAbstract:Insulin resistance is associated with both obesity and hypertension. However, the cellular mechanisms of insulin resistance in genetic models of obese-hypertension have not been identified. The obj...
