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Roger H Unger - One of the best experts on this subject based on the ideXlab platform.

  • gluttony sloth and the metabolic syndrome a roadmap to lipotoxicity
    Trends in Endocrinology and Metabolism, 2010
    Co-Authors: Roger H Unger, Philipp E. Scherer
    Abstract:

    Once considered divine retribution for sins, comorbidities of obesity (metabolic syndrome) are today attributed to obesity-induced metabolic defects. Here, we propose that obesity and Hyperleptinemia protect lipid-intolerant nonadipose organs against lipotoxic lipid spillover during sustained caloric surplus. Metabolic syndrome is ascribed to lipotoxicity caused by age-related resistance to antilipotoxic protection by leptin.

  • combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats implications for obesity treatment
    Journal of Biological Chemistry, 2006
    Co-Authors: Byung Hyun Park, Mayyun Wang, Xinxin Yu, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Abstract Intense Hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted all fat from native fat pads and from fat transplants from +/+ donors but not from transplants from ZDFfa/fa donors with defective leptin receptors. In both native and transplanted +/+ fat pads, large numbers of mitochondria were apparent, and genes involved in fatty acid oxidation were up-regulated. However, +/+ fat pads transplanted into fa/fa recipients did not respond to Hyperleptinemia, suggesting lack of an essential leptin-stimulated cohormone(s). In +/+ but not in fa/fa rats, plasma catecholamine levels rose, and both P-STAT3 and P-CREB increased in adipose tissue, suggesting that both direct and indirect (hypothalamic) leptin receptor-mediated actions of Hyperleptinemia are involved in depletion of adipocyte fat.

  • combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats implications for obesity treatment
    Journal of Biological Chemistry, 2006
    Co-Authors: Byung Hyun Park, Mayyun Wang, Xinxin Yu, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Abstract Intense Hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted all fat from native fat pads and from fat transplants from +/+ donors but not from transplants from ZDFfa/fa donors with defective leptin receptors. In both native and transplanted +/+ fat pads, large numbers of mitochondria were apparent, and genes involved in fatty acid oxidation were up-regulated. However, +/+ fat pads transplanted into fa/fa recipients did not respond to Hyperleptinemia, suggesting lack of an essential leptin-stimulated cohormone(s). In +/+ but not in fa/fa rats, plasma catecholamine levels rose, and both P-STAT3 and P-CREB increased in adipose tissue, suggesting that both direct and indirect (hypothalamic) leptin receptor-mediated actions of Hyperleptinemia are involved in depletion of adipocyte fat.

  • fat storage in adipocytes requires inactivation of leptin s paracrine activity implications for treatment of human obesity
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Mayyun Wang, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable Hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-γ-coactivator-1α, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.

  • longevity lipotoxicity and leptin the adipocyte defense against feasting and famine
    Biochimie, 2005
    Co-Authors: Roger H Unger
    Abstract:

    Abstract In this review, we propose that actions of the lipid-lowering, apoptosis-inhibiting effects of certain “longevity genes” oppose the life-shortening consequences of lipotoxicity and lipoapoptosis. We note that lipotoxicity occurs whenever leptin action is deficient, or whenever satiety is overridden, as in forced or voluntary overfeeding (“supersizing”). The role of Hyperleptinemia, we suggest, is to extend survival during famine by permitting the storage of surplus calories in adipocytes without concomitant injury to nonadipose tissues from ectopic lipid deposits. It achieves this lipid partitioning by (1) restraining the level of overnutrition so as not to exceed the available adipocyte storage space and (2) enhancing oxidation of any ectopic lipid overflow: The mechanisms of lipoapoptosis are discussed, and the possibility that metabolic syndrome is the human equivalent of rodent lipotoxicity is suggested.

Mayyun Wang - One of the best experts on this subject based on the ideXlab platform.

  • combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats implications for obesity treatment
    Journal of Biological Chemistry, 2006
    Co-Authors: Byung Hyun Park, Mayyun Wang, Xinxin Yu, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Abstract Intense Hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted all fat from native fat pads and from fat transplants from +/+ donors but not from transplants from ZDFfa/fa donors with defective leptin receptors. In both native and transplanted +/+ fat pads, large numbers of mitochondria were apparent, and genes involved in fatty acid oxidation were up-regulated. However, +/+ fat pads transplanted into fa/fa recipients did not respond to Hyperleptinemia, suggesting lack of an essential leptin-stimulated cohormone(s). In +/+ but not in fa/fa rats, plasma catecholamine levels rose, and both P-STAT3 and P-CREB increased in adipose tissue, suggesting that both direct and indirect (hypothalamic) leptin receptor-mediated actions of Hyperleptinemia are involved in depletion of adipocyte fat.

  • combined leptin actions on adipose tissue and hypothalamus are required to deplete adipocyte fat in lean rats implications for obesity treatment
    Journal of Biological Chemistry, 2006
    Co-Authors: Byung Hyun Park, Mayyun Wang, Xinxin Yu, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Abstract Intense Hyperleptinemia completely depletes adipocyte fat of normal rats within 14 days. To determine the mechanism, epididymal fat pads from normal wild-type (+/+) and obese (fa/fa) Zucker Diabetic Fatty (ZDF) donor rats were transplanted into normal +/+ and fa/fa ZDF recipients. Hyperleptinemia induced by adenovirus-leptin administration depleted all fat from native fat pads and from fat transplants from +/+ donors but not from transplants from ZDFfa/fa donors with defective leptin receptors. In both native and transplanted +/+ fat pads, large numbers of mitochondria were apparent, and genes involved in fatty acid oxidation were up-regulated. However, +/+ fat pads transplanted into fa/fa recipients did not respond to Hyperleptinemia, suggesting lack of an essential leptin-stimulated cohormone(s). In +/+ but not in fa/fa rats, plasma catecholamine levels rose, and both P-STAT3 and P-CREB increased in adipose tissue, suggesting that both direct and indirect (hypothalamic) leptin receptor-mediated actions of Hyperleptinemia are involved in depletion of adipocyte fat.

  • fat storage in adipocytes requires inactivation of leptin s paracrine activity implications for treatment of human obesity
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Mayyun Wang, Lelio Orci, Mariella Ravazzola, Roger H Unger
    Abstract:

    Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable Hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-γ-coactivator-1α, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.

  • pparα is necessary for the lipopenic action of Hyperleptinemia on white adipose and liver tissue
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Young Hee Lee, Mayyun Wang, F Gonzales, David J Mangelsdorf, C Richardson, Lee A Witters, Roger H Unger
    Abstract:

    Adenovirus-induced Hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)α expression, which was increased during the rapid loss of fat, we infused adenovirus–leptin into PPARα−/− and PPARα+/+ mice. Despite similar degrees of Hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPARα−/− mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR−/− mice. Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPARα−/− mice. PPARγ coactivator-1α rose 3-fold in the fat and 46% in the liver of wild-type mice but was unchanged in PPARα−/− mice. Although AMP-activated protein kinase could not be implicated in the lipopenic actions of Hyperleptinemia, acetyl CoA carboxylase protein was reduced in the liver of wild-type but not in PPARα−/− mice. Thus, in PPARα−/− mice, up-regulation of carnitine palmitoyl transferase-1 mRNA in fat, down-regulation of acetyl CoA carboxylase in liver, and up-regulation of PPARγ coactivator-1α mRNA in both tissues are abolished, as is the reduction in their triacylglycerol content.

  • liporegulation in diet induced obesity the antisteatotic role of Hyperleptinemia
    Journal of Biological Chemistry, 2001
    Co-Authors: Young Hee Lee, Mayyun Wang, Roger H Unger, Yan Ting Zhou, Tetsuya Kakuma, Zhuo Wei Wang, Evelyn E Babcock, K Mccorkle, Moritake Higa
    Abstract:

    To test the hypothesis that the physiologic liporegulatory role of Hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an approximately 150-fold increase in body fat (r = 0.91, p < 0.0001). During this time, the triacylglycerol (TG) content of nonadipose tissues rose only 1-2.7-fold implying antisteatotic activity. In rodents without leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% fat diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 60% fat diet, peroxisome proliferator-activated receptor alpha protein and liver-carnitine palmitoyltransferase-1 (l-CPT-1) mRNA increased in liver. In their pancreatic islets, fatty-acid oxidation increased 30% without detectable increase in the expression of peroxisome proliferator-activated receptor-alpha or oxidative enzymes, whereas lipogenesis from [14C]glucose was slightly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpression of wild-type leptin receptors in the livers of fa/fa rats, in which marked steatosis is uniformly present, reduced TG accumulation in liver but nowhere else. We conclude that a physiologic role of the Hyperleptinemia of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and increasing fatty-acid oxidation.

Patricia Cristina Lisboa - One of the best experts on this subject based on the ideXlab platform.

  • ilex paraguariensis yerba mate improves endocrine and metabolic disorders in obese rats primed by early weaning
    European Journal of Nutrition, 2014
    Co-Authors: Natalia Da Silva Lima, Juliana G Franco, Egberto Gaspar De Moura, Elaine De Oliveira, Ligia De Albuquerque Maia, Nayara Peixotosilva, Andrea Kaezer, Israel Felzenszwalb, Patricia Cristina Lisboa
    Abstract:

    Purpose We showed that early weaned rats developed obesity, Hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.

  • higher white adipocyte area and lower leptin production in adult rats overfed during lactation
    Hormone and Metabolic Research, 2011
    Co-Authors: E P S Conceicao, I H Trevenzoli, E Oliveira, Juliana G Franco, Aluana Santana Carlos, Celly Cristina Alves Do Nascimentosaba, Egberto Gaspar De Moura, Patricia Cristina Lisboa
    Abstract:

    Litter size reduction during lactation is a good model for childhood obesity since it induces overnutrition and programming for obesity at adulthood. Adult offspring develop higher fat mass content, hyperinsulinemia and insulin resistance, hypertension, lower HDL cholesterol, hyperphagia, and leptin resistance. Leptin resistance is often associated with Hyperleptinemia. Although we observed higher SOCS3 and lower STAT3 in the hypothalamus of rats raised in small litters featuring a central leptin resistance, they showed unexpected normoleptinemia at 180 days old. Then, to clarify why early overfed rats did not develop Hyperleptinemia when adult, we studied the leptin production by the visceral and subcutaneous adipose tissue and skeletal muscle as well as the morphology in the 2 different fat depots. To induce EO, litter size was reduced to 3 pups/litter (SL group) on the 3 rd day of life. In controls (NL group), litter size was adjusted to 10 pups/litter. Rats were killed at 180 days old. The programming of adipose tissue morphology by early overnutrition is specific between the different fat depots with hypertrophy only in the visceral compartment. In addition, the visceral adipocyte showed lower leptin content that may indicate a reduced leptin synthesis. These data suggest that adipocytes from SL rats are dysfunctional, since a higher leptin production in larger adipose cells is expected. In conclusion, postnatal nutrition is determinant for future leptin production by different fat depots as well as adipocyte morphology. These changes seem to be related to the severity of obesity and its metabolic consequences.

  • postnatal early overfeeding induces hypothalamic higher socs3 expression and lower stat3 activity in adult rats
    Journal of Nutritional Biochemistry, 2011
    Co-Authors: Ananda Lages Rodrigues, E P S Conceicao, I H Trevenzoli, Egberto Gaspar De Moura, Magna Cottini Fonseca Passos, Isabela Teixeira Bonono, Jose Firmino Nogueira Neto, Patricia Cristina Lisboa
    Abstract:

    Postnatal early overnutrition (EO) is a risk factor for future obesity and metabolic disorders. Rats raised in small litters (SLs) develop overweight, hyperphagia, Hyperleptinemia, hyperinsulinemia and hypertension when adults. As obesity is related to Hyperleptinemia, leptin resistance and metabolic syndrome, we aimed to investigate body composition, plasma hormone levels, glucose tolerance and the leptin signaling pathway in hypothalamus from early overfed animals at weaning and adulthood. To induce postnatal EO, we reduced litter size to three pups/litter (SL), and the groups with normal litter size (10 pups/litter) were used as control. Rats had free access to standard diet and water postweaning. Body weight and food intake were monitored daily, and offspring were killed at 21 (weaning) and 180 days old (adulthood). Postnatal EO group had higher body weight and total and visceral fat mass at both periods. Lean mass and serum high-density lipoprotein cholesterol (HDL-C) were higher at 21 days and lower at 180 days. Small litter rats presented higher levels of globulins at both periods, while albumin levels were higher at weaning and lower at adulthood. There was higher leptin, insulin and glucose serum concentrations at 21 days old, while no glucose intolerance was observed in adulthood. Leptin signaling pathway was unaffected at weaning. However, postnatal EO induced lower JAK2 and p-STAT3, and higher SOCS3 expression in adult animals, indicating central leptin resistance in adulthood. In conclusion, postnatal EO induces obesity, higher total and visceral fat mass, lower HDL-C and central leptin resistance in adult life.

  • thyroid function and body weight programming by neonatal hyperthyroidism in rats the role of leptin and deiodinase activities
    Hormone and Metabolic Research, 2008
    Co-Authors: Egberto Gaspar De Moura, E Oliveira, Patricia Cristina Lisboa, A. T. S. Fagundes, I T Bonomo, R S Santos, S B Alves, M C F Passos
    Abstract:

    Several authors have shown that secondary hypothyroidism was programed by neonatal thyroxine (T 4 ) treatment. However, the associated changes of body weight (BW) were less studied, especially those related to the body fat proportion. Here, we have evaluated the effect of neonatal thyroxine treatment on BW, fat proportion, serum leptin, and thyroid function of 60-day-old rats. Wistar rats were treated with thyroxine (50 μg/100 g BW, ip) (T) or saline (S), during the first 10 days of life. BW, nose-rump length (NRL), and food consumption were monitored for 60 days, when the animals were sacrificed. Thyroid function was evaluated by thyroid radioiodine uptake (RAIU), serum T 3 , T 4 , TSH, and liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD) and type 1 and 2 deiodinases (D1 and D2) activities, which are thyroid hormone-dependent enzymes. T animals showed lower food intake, BW and NRL, but higher total fat mass (+33%) and serum leptin (+46%). They also showed lower serum T3 (-23%), T4 (-32%), TSH (-36%), RAIU (-29%) and mGPD activity (-22%). Hypothalamic and pituitary D2 activities were higher (+24% and 1.4 fold, respectively), while brown adipose tissue (BAT) D2 and skeletal muscle D1 activities were lower (-30% and -62%, respectively). Thus, neonatal hyperthyroidism programs for a higher fat proportion and Hyperleptinemia, which can explain the lower food intake. The TH-dependent enzymes activities changed accordingly, except for the decrease in BAT D2, which may be due the role played by the Hyperleptinemia. Finally, the decrease in peripheral deiodination may contribute to a lower me-tabolic rate that may increase the adiposity.

  • leptin and prolactin but not corticosterone modulate body weight and thyroid function in protein malnourished lactating rats
    Hormone and Metabolic Research, 2006
    Co-Authors: Patricia Cristina Lisboa, M C F Passos, S C P Dutra, I T Bonomo, A T A Denolato, Adelina M Reis, Egberto Gaspar De Moura
    Abstract:

    To understand the role of hormonal changes in the lower food ingestion and body weight in protein-restricted lactating rats as well as the higher serum T (3), higher deiodination, iodide and T (3) milk transfer, we measured maternal serum prolactin, leptin, TSH and corticosterone, which are hormones that could influence those parameters. After birth, dams were separated into: control-fed with a 23 % protein diet (n = 12) and PR (protein-restricted)-fed with an 8 % protein diet (n = 12). At the 4 (th) and 21 (st) day of lactation, half of the animals in each group were sacrificed. PR dams presented Hyperleptinemia (day 4: + 20 %; day 21: + 19 %; p < 0.05) and hypoprolactinemia (day 4: - 85 %; day 21: - 92 %; p < 0.05), which could help explain the lower food consumption and body weight in lactating PR rats since leptin is anorexigenic and prolactin is orexigenic. Also, this Hyperleptinemia could contribute for the increase in serum T (3) of PR dams, since leptin stimulates T (3) production, especially acting on deiodinases. Serum corticosterone was not different between PR and C groups, and TSH was lower only at the end of lactation. Thus, we suggest that both leptin and prolactin could play an important role in the body weight and thyroid hormone changes observed in protein-malnourished lactating rats.

Young Hee Lee - One of the best experts on this subject based on the ideXlab platform.

  • pparα is necessary for the lipopenic action of Hyperleptinemia on white adipose and liver tissue
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Young Hee Lee, Mayyun Wang, F Gonzales, David J Mangelsdorf, C Richardson, Lee A Witters, Roger H Unger
    Abstract:

    Adenovirus-induced Hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)α expression, which was increased during the rapid loss of fat, we infused adenovirus–leptin into PPARα−/− and PPARα+/+ mice. Despite similar degrees of Hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPARα−/− mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR−/− mice. Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPARα−/− mice. PPARγ coactivator-1α rose 3-fold in the fat and 46% in the liver of wild-type mice but was unchanged in PPARα−/− mice. Although AMP-activated protein kinase could not be implicated in the lipopenic actions of Hyperleptinemia, acetyl CoA carboxylase protein was reduced in the liver of wild-type but not in PPARα−/− mice. Thus, in PPARα−/− mice, up-regulation of carnitine palmitoyl transferase-1 mRNA in fat, down-regulation of acetyl CoA carboxylase in liver, and up-regulation of PPARγ coactivator-1α mRNA in both tissues are abolished, as is the reduction in their triacylglycerol content.

  • liporegulation in diet induced obesity the antisteatotic role of Hyperleptinemia
    Journal of Biological Chemistry, 2001
    Co-Authors: Young Hee Lee, Mayyun Wang, Roger H Unger, Yan Ting Zhou, Tetsuya Kakuma, Zhuo Wei Wang, Evelyn E Babcock, K Mccorkle, Moritake Higa
    Abstract:

    To test the hypothesis that the physiologic liporegulatory role of Hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an approximately 150-fold increase in body fat (r = 0.91, p < 0.0001). During this time, the triacylglycerol (TG) content of nonadipose tissues rose only 1-2.7-fold implying antisteatotic activity. In rodents without leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% fat diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 60% fat diet, peroxisome proliferator-activated receptor alpha protein and liver-carnitine palmitoyltransferase-1 (l-CPT-1) mRNA increased in liver. In their pancreatic islets, fatty-acid oxidation increased 30% without detectable increase in the expression of peroxisome proliferator-activated receptor-alpha or oxidative enzymes, whereas lipogenesis from [14C]glucose was slightly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpression of wild-type leptin receptors in the livers of fa/fa rats, in which marked steatosis is uniformly present, reduced TG accumulation in liver but nowhere else. We conclude that a physiologic role of the Hyperleptinemia of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and increasing fatty-acid oxidation.

  • leptin troglitazone and the expression of sterol regulatory element binding proteins in liver and pancreatic islets
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Tetsuya Kakuma, Young Hee Lee, Zhuo Wei Wang, Moritake Higa, Wentong Pan, Iichiro Shimomura, Roger H Unger
    Abstract:

    Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague–Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced Hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.

  • disappearance of body fat in normal rats induced by adenovirus mediated leptin gene therapy
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Guoxun Chen, Kazunori Koyama, Xue Yuan, Young Hee Lee, Yan Ting Zhou, Robert M Odoherty, Christopher B Newgard, Roger H Unger
    Abstract:

    Sustained Hyperleptinemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin). Hyperleptinemic rats exhibited a 30–50% reduction in food intake and gained only 22 g over the experimental period versus 115–132 g in control animals that received saline infusions or a recombinant virus containing the β-galactosidase gene (AdCMV-βGal). Body fat was absent in hyperleptinemic rats, whereas control rats pair-fed to the hyperleptinemic rats retained ≈50% body fat. Further, plasma triglycerides and insulin levels were significantly lower in hyperleptinemic versus pair-fed controls, while fatty acid and glucose levels were similar in the two groups, suggestive of enhanced insulin sensitivity in the hyperleptinemic animals. Thus, despite equivalent reductions in food intake and weight gain in hyperleptinemic and pair-fed animals, identifiable fat tissue was completely ablated only in the former group, raising the possibility of a specific lipoatrophic activity for leptin.

Egberto Gaspar De Moura - One of the best experts on this subject based on the ideXlab platform.

  • ilex paraguariensis yerba mate improves endocrine and metabolic disorders in obese rats primed by early weaning
    European Journal of Nutrition, 2014
    Co-Authors: Natalia Da Silva Lima, Juliana G Franco, Egberto Gaspar De Moura, Elaine De Oliveira, Ligia De Albuquerque Maia, Nayara Peixotosilva, Andrea Kaezer, Israel Felzenszwalb, Patricia Cristina Lisboa
    Abstract:

    Purpose We showed that early weaned rats developed obesity, Hyperleptinemia, leptin and insulin resistance at adulthood. Here, we studied the potential beneficial effects of Ilex paraguariensis aqueous solution upon body composition, glycemia, lipid and hormonal profiles, leptin signaling and NPY content.

  • higher white adipocyte area and lower leptin production in adult rats overfed during lactation
    Hormone and Metabolic Research, 2011
    Co-Authors: E P S Conceicao, I H Trevenzoli, E Oliveira, Juliana G Franco, Aluana Santana Carlos, Celly Cristina Alves Do Nascimentosaba, Egberto Gaspar De Moura, Patricia Cristina Lisboa
    Abstract:

    Litter size reduction during lactation is a good model for childhood obesity since it induces overnutrition and programming for obesity at adulthood. Adult offspring develop higher fat mass content, hyperinsulinemia and insulin resistance, hypertension, lower HDL cholesterol, hyperphagia, and leptin resistance. Leptin resistance is often associated with Hyperleptinemia. Although we observed higher SOCS3 and lower STAT3 in the hypothalamus of rats raised in small litters featuring a central leptin resistance, they showed unexpected normoleptinemia at 180 days old. Then, to clarify why early overfed rats did not develop Hyperleptinemia when adult, we studied the leptin production by the visceral and subcutaneous adipose tissue and skeletal muscle as well as the morphology in the 2 different fat depots. To induce EO, litter size was reduced to 3 pups/litter (SL group) on the 3 rd day of life. In controls (NL group), litter size was adjusted to 10 pups/litter. Rats were killed at 180 days old. The programming of adipose tissue morphology by early overnutrition is specific between the different fat depots with hypertrophy only in the visceral compartment. In addition, the visceral adipocyte showed lower leptin content that may indicate a reduced leptin synthesis. These data suggest that adipocytes from SL rats are dysfunctional, since a higher leptin production in larger adipose cells is expected. In conclusion, postnatal nutrition is determinant for future leptin production by different fat depots as well as adipocyte morphology. These changes seem to be related to the severity of obesity and its metabolic consequences.

  • postnatal early overfeeding induces hypothalamic higher socs3 expression and lower stat3 activity in adult rats
    Journal of Nutritional Biochemistry, 2011
    Co-Authors: Ananda Lages Rodrigues, E P S Conceicao, I H Trevenzoli, Egberto Gaspar De Moura, Magna Cottini Fonseca Passos, Isabela Teixeira Bonono, Jose Firmino Nogueira Neto, Patricia Cristina Lisboa
    Abstract:

    Postnatal early overnutrition (EO) is a risk factor for future obesity and metabolic disorders. Rats raised in small litters (SLs) develop overweight, hyperphagia, Hyperleptinemia, hyperinsulinemia and hypertension when adults. As obesity is related to Hyperleptinemia, leptin resistance and metabolic syndrome, we aimed to investigate body composition, plasma hormone levels, glucose tolerance and the leptin signaling pathway in hypothalamus from early overfed animals at weaning and adulthood. To induce postnatal EO, we reduced litter size to three pups/litter (SL), and the groups with normal litter size (10 pups/litter) were used as control. Rats had free access to standard diet and water postweaning. Body weight and food intake were monitored daily, and offspring were killed at 21 (weaning) and 180 days old (adulthood). Postnatal EO group had higher body weight and total and visceral fat mass at both periods. Lean mass and serum high-density lipoprotein cholesterol (HDL-C) were higher at 21 days and lower at 180 days. Small litter rats presented higher levels of globulins at both periods, while albumin levels were higher at weaning and lower at adulthood. There was higher leptin, insulin and glucose serum concentrations at 21 days old, while no glucose intolerance was observed in adulthood. Leptin signaling pathway was unaffected at weaning. However, postnatal EO induced lower JAK2 and p-STAT3, and higher SOCS3 expression in adult animals, indicating central leptin resistance in adulthood. In conclusion, postnatal EO induces obesity, higher total and visceral fat mass, lower HDL-C and central leptin resistance in adult life.

  • thyroid function and body weight programming by neonatal hyperthyroidism in rats the role of leptin and deiodinase activities
    Hormone and Metabolic Research, 2008
    Co-Authors: Egberto Gaspar De Moura, E Oliveira, Patricia Cristina Lisboa, A. T. S. Fagundes, I T Bonomo, R S Santos, S B Alves, M C F Passos
    Abstract:

    Several authors have shown that secondary hypothyroidism was programed by neonatal thyroxine (T 4 ) treatment. However, the associated changes of body weight (BW) were less studied, especially those related to the body fat proportion. Here, we have evaluated the effect of neonatal thyroxine treatment on BW, fat proportion, serum leptin, and thyroid function of 60-day-old rats. Wistar rats were treated with thyroxine (50 μg/100 g BW, ip) (T) or saline (S), during the first 10 days of life. BW, nose-rump length (NRL), and food consumption were monitored for 60 days, when the animals were sacrificed. Thyroid function was evaluated by thyroid radioiodine uptake (RAIU), serum T 3 , T 4 , TSH, and liver mitochondrial alpha-glycerophosphate dehydrogenase (mGPD) and type 1 and 2 deiodinases (D1 and D2) activities, which are thyroid hormone-dependent enzymes. T animals showed lower food intake, BW and NRL, but higher total fat mass (+33%) and serum leptin (+46%). They also showed lower serum T3 (-23%), T4 (-32%), TSH (-36%), RAIU (-29%) and mGPD activity (-22%). Hypothalamic and pituitary D2 activities were higher (+24% and 1.4 fold, respectively), while brown adipose tissue (BAT) D2 and skeletal muscle D1 activities were lower (-30% and -62%, respectively). Thus, neonatal hyperthyroidism programs for a higher fat proportion and Hyperleptinemia, which can explain the lower food intake. The TH-dependent enzymes activities changed accordingly, except for the decrease in BAT D2, which may be due the role played by the Hyperleptinemia. Finally, the decrease in peripheral deiodination may contribute to a lower me-tabolic rate that may increase the adiposity.

  • leptin and prolactin but not corticosterone modulate body weight and thyroid function in protein malnourished lactating rats
    Hormone and Metabolic Research, 2006
    Co-Authors: Patricia Cristina Lisboa, M C F Passos, S C P Dutra, I T Bonomo, A T A Denolato, Adelina M Reis, Egberto Gaspar De Moura
    Abstract:

    To understand the role of hormonal changes in the lower food ingestion and body weight in protein-restricted lactating rats as well as the higher serum T (3), higher deiodination, iodide and T (3) milk transfer, we measured maternal serum prolactin, leptin, TSH and corticosterone, which are hormones that could influence those parameters. After birth, dams were separated into: control-fed with a 23 % protein diet (n = 12) and PR (protein-restricted)-fed with an 8 % protein diet (n = 12). At the 4 (th) and 21 (st) day of lactation, half of the animals in each group were sacrificed. PR dams presented Hyperleptinemia (day 4: + 20 %; day 21: + 19 %; p < 0.05) and hypoprolactinemia (day 4: - 85 %; day 21: - 92 %; p < 0.05), which could help explain the lower food consumption and body weight in lactating PR rats since leptin is anorexigenic and prolactin is orexigenic. Also, this Hyperleptinemia could contribute for the increase in serum T (3) of PR dams, since leptin stimulates T (3) production, especially acting on deiodinases. Serum corticosterone was not different between PR and C groups, and TSH was lower only at the end of lactation. Thus, we suggest that both leptin and prolactin could play an important role in the body weight and thyroid hormone changes observed in protein-malnourished lactating rats.