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Article ; Online: Systemic SIRT1 insufficiency results in disruption of energy homeostasis and steroid hormone metabolism upon high-fat-diet feeding.

Purushotham, Aparna / Xu, Qing / Li, Xiaoling

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2011 Volume 26, Issue 2, Page(s) 656–667

Abstract: SIRT1 is a highly-conserved NAD(+)-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in ... ...

Abstract	SIRT1 is a highly-conserved NAD(+)-dependent protein deacetylase that plays essential roles in the regulation of energy metabolism, genomic stability, and stress response. Although the functions of SIRT1 in many organs have been extensively studied in tissue-specific knockout mouse models, the systemic role of SIRT1 is still largely unknown as a result of severe developmental defects that result from whole-body knockout in mice. Here, we investigated the systemic functions of SIRT1 in metabolic homeostasis by utilizing a whole-body SIRT1 heterozygous mouse model. These mice are phenotypically normal under standard feeding conditions. However, when chronically challenged with a 40% fat diet, they become obese and insulin resistant, display increased serum cytokine levels, and develop hepatomegaly. Hepatic metabolomic analyses revealed that SIRT1 heterozygous mice have elevated gluconeogenesis and oxidative stress. Surprisingly, they are depleted of glycerolipid metabolites and free fatty acids, yet accumulate lysolipids. Moreover, high-fat feeding induces elevation of serum testosterone levels and enlargement of seminal vesicles in SIRT1 heterozygous males. Microarray analysis of liver mRNA indicates that they have altered expression of genes involved in steroid metabolism and glycerolipid metabolism. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of systemic energy and steroid hormone homeostasis.
MeSH term(s)	Animals ; Cytokines/blood ; Diet, High-Fat/adverse effects ; Energy Metabolism ; Fatty Acids, Nonesterified/metabolism ; Gene Expression Profiling ; Gluconeogenesis ; Glycolipids/metabolism ; Heterozygote ; Homeostasis ; Hyperandrogenism/etiology ; Hyperandrogenism/genetics ; Hyperandrogenism/metabolism ; Insulin Resistance ; Liver/metabolism ; Male ; Metabolome ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/etiology ; Obesity/genetics ; Obesity/metabolism ; Sirtuin 1/deficiency ; Sirtuin 1/genetics ; Sirtuin 1/metabolism ; Steroids/metabolism
Chemical Substances	Cytokines ; Fatty Acids, Nonesterified ; Glycolipids ; Steroids ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2011-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.11-195172
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Zs.A 2266: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 296: Show issues

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Article ; Online: SIRT1 performs a balancing act on the tight-rope toward longevity.

Purushotham, Aparna / Schug, Thaddeus T / Li, Xiaoling

Aging

2009 Volume 1, Issue 7, Page(s) 669–673

Abstract: Our recent study defined a new role for SIRT1 as a regulator of hepatic lipid metabolism. In the liver a major target of this sirtuin is the PPARalpha/PGC-1alpha signaling axis. Ablation of SIRT1 in the liver results in disrupted fatty acid oxidation, ... ...

Abstract	Our recent study defined a new role for SIRT1 as a regulator of hepatic lipid metabolism. In the liver a major target of this sirtuin is the PPARalpha/PGC-1alpha signaling axis. Ablation of SIRT1 in the liver results in disrupted fatty acid oxidation, increased cellular stress, and elevations in proinflammatory cytokines. However, contrary to previous studies, we observed no changes in glucose production in the absence of SIRT1, despite impaired PGC-1alpha signaling. These findings point toward the involvement of other players in SIRT1-regulated hepatic metabolism. Here we discuss our findings, and comment on some of the controversy surrounding this protein in the current literature.
MeSH term(s)	Animals ; Cytokines/metabolism ; Fatty Acids/metabolism ; Gluconeogenesis/physiology ; Humans ; Lipid Metabolism/physiology ; Liver/metabolism ; Longevity/physiology ; Mice ; Mice, Knockout ; Oxidation-Reduction ; PPAR alpha/genetics ; PPAR alpha/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Sirtuin 1/genetics ; Sirtuin 1/metabolism ; Stress, Physiological/physiology ; Trans-Activators/metabolism ; Transcription Factors
Chemical Substances	Cytokines ; Fatty Acids ; PPAR alpha ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ppargc1a protein, mouse ; Trans-Activators ; Transcription Factors ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2009-07-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.100076
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Article ; Online: The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells.

Purushotham, Aparna / Tian, Min / Belury, Martha A

Molecular nutrition & food research

2009 Volume 53, Issue 2, Page(s) 300–307

Abstract: Hepatic gluconeogenesis is the major source of fasting hyperglycemia. Here, we investigated the role of the citrus fruit flavonoid naringenin, in the attenuation of hepatic glucose production from hepatoma (Fao) cells. We show that naringenin, but not ... ...

Abstract	Hepatic gluconeogenesis is the major source of fasting hyperglycemia. Here, we investigated the role of the citrus fruit flavonoid naringenin, in the attenuation of hepatic glucose production from hepatoma (Fao) cells. We show that naringenin, but not its glucoside naringin, suppresses hepatic glucose production. Furthermore, unlike insulin-mediated suppression of hepatic glucose production, incubation of hepatocytes with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor Ly294002 had no effect on the ability of naringenin to suppress hepatic glucose production. Further, naringenin did not increase phosphorylation of Akt at Ser473 or, Thr308, indicating this down-stream target of PI3-kinase is also not a player in naringenin-mediated suppression of hepatic glucose production. Importantly, like the dimethylbiguanide, metformin, naringenin significantly decreased cellular ATP levels without increasing cell cytotoxicity. Together, these results suggest that the aglycone, naringenin, has a role in the attenuation of hyperglycemia and may exert this effect in a manner similar to the drug, metformin.
MeSH term(s)	Animals ; Dose-Response Relationship, Drug ; Flavanones/pharmacology ; Glucose/metabolism ; Glucose-6-Phosphatase/genetics ; Hypoglycemic Agents/pharmacology ; Liver/metabolism ; Liver Neoplasms, Experimental/metabolism ; Metformin/pharmacology ; Phosphatidylinositol 3-Kinases/physiology ; Phosphoenolpyruvate Carboxykinase (GTP)/genetics ; Rats ; Signal Transduction
Chemical Substances	Flavanones ; Hypoglycemic Agents ; Metformin (9100L32L2N) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Glucose-6-Phosphatase (EC 3.1.3.9) ; Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) ; naringenin (HN5425SBF2) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2009-02
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2160372-8
ISSN	1613-4133 ; 1613-4125
ISSN (online)	1613-4133
ISSN	1613-4125
DOI	10.1002/mnfr.200700514
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Article: The citrus fruit flavonoid naringenin suppresses hepatic glucose production from Fao hepatoma cells

Purushotham, Aparna / Tian, Min / Belury, Martha.A

Molecular nutrition & food research. 2009 Feb., v. 53, no. 2

2009

Abstract	Hepatic gluconeogenesis is the major source of fasting hyperglycemia. Here, we investigated the role of the citrus fruit flavonoid naringenin, in the attenuation of hepatic glucose production from hepatoma (Fao) cells. We show that naringenin, but not its glucoside naringin, suppresses hepatic glucose production. Furthermore, unlike insulin-mediated suppression of hepatic glucose production, incubation of hepatocytes with the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor Ly294002 had no effect on the ability of naringenin to suppress hepatic glucose production. Further, naringenin did not increase phosphorylation of Akt at Ser473 or, Thr308, indicating this down-stream target of PI3-kinase is also not a player in naringenin-mediated suppression of hepatic glucose production. Importantly, like the dimethylbiguanide, metformin, naringenin significantly decreased cellular ATP levels without increasing cell cytotoxicity. Together, these results suggest that the aglycone, naringenin, has a role in the attenuation of hyperglycemia and may exert this effect in a manner similar to the drug, metformin.
Keywords	adenosine triphosphate ; citrus fruits ; cytotoxicity ; gluconeogenesis ; glucose ; hepatoma ; hyperglycemia ; metformin ; naringenin ; naringin ; phosphatidylinositol 3-kinase ; phosphorylation
Language	English
Dates of publication	2009-02
Size	p. 300-307.
Publishing place	Wiley-VCH Verlag
Document type	Article
ZDB-ID	2160372-8
ISSN	1613-4133 ; 1613-4125
ISSN (online)	1613-4133
ISSN	1613-4125
DOI	10.1002/mnfr.200700514
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Article ; Online: Conjugated linoleic acid induces uncoupling protein 1 in white adipose tissue of ob/ob mice.

Wendel, Angela A / Purushotham, Aparna / Liu, Li-Fen / Belury, Martha A

Lipids

2009 Volume 44, Issue 11, Page(s) 975–982

Abstract: Conjugated linoleic acid (CLA) reduces body weight and adipose mass in a variety of species. The mechanisms by which CLA depletes adipose mass are unclear, but two independent microarray analyses indicate that in white adipose tissue (WAT), uncoupling ... ...

Abstract	Conjugated linoleic acid (CLA) reduces body weight and adipose mass in a variety of species. The mechanisms by which CLA depletes adipose mass are unclear, but two independent microarray analyses indicate that in white adipose tissue (WAT), uncoupling protein 1 (UCP1) was among genes most changed by CLA. The objective of this study was to determine whether CLA induces ectopic expression of UCP1 in WAT, which may contribute to increased energy expenditure and weight loss. Six-week old, male ob/ob mice were fed either a control diet (CON) or a diet supplemented with 1.5% mixed isomer CLA (CLA) for 4 weeks. A third group of mice (LEPTIN) was fed the control diet and received daily injections of recombinant leptin as a positive control for adipose depletion in ob/ob mice. CLA did not alter several mRNA markers of lipid oxidation in epididymal white adipose tissue (eWAT) , but significantly increased carnitine palmitoyltransferase-1b (CPT1b) and PPAR gamma coactivator-1alpha (PGC1alpha) expression. Notably, CLA increased both mRNA and protein expression of uncoupling protein-1 (UCP1). beta3-adrenoceptor mRNA and phosphorylated-p38 mitogen activated protein kinase (MAPK) protein levels were not affected by CLA, but were upregulated by LEPTIN. These data suggest the increased CPT1b, PGC1alpha, and UCP1, in WAT of CLA-fed mice may contribute to the depletion of adipose, and CLA does not appear to increase UCP1 through beta3-adrenergic signaling. Future studies will focus on understanding how CLA increases mitochondrial oxidation and energy dissipation in white adipose tissue.
MeSH term(s)	Adipose Tissue, White/drug effects ; Adipose Tissue, White/metabolism ; Animals ; Body Weight ; Carnitine O-Palmitoyltransferase/genetics ; Carnitine O-Palmitoyltransferase/metabolism ; Energy Metabolism ; Ion Channels/genetics ; Ion Channels/metabolism ; Leptin/metabolism ; Linoleic Acids, Conjugated/pharmacology ; Male ; Mice ; Mice, Transgenic ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Obesity/genetics ; Obesity/metabolism ; RNA, Messenger/metabolism ; Uncoupling Protein 1
Chemical Substances	Ion Channels ; Leptin ; Linoleic Acids, Conjugated ; Mitochondrial Proteins ; RNA, Messenger ; UCP1 protein, human ; Ucp1 protein, mouse ; Uncoupling Protein 1 ; Carnitine O-Palmitoyltransferase (EC 2.3.1.21)
Language	English
Publishing date	2009-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	241539-2
ISSN	1558-9307 ; 0024-4201
ISSN (online)	1558-9307
ISSN	0024-4201
DOI	10.1007/s11745-009-3348-9
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Article: Conjugated linoleic acid fails to worsen insulin resistance but induces hepatic steatosis in the presence of leptin in ob/ob mice.

Wendel, Angela A / Purushotham, Aparna / Liu, Li-Fen / Belury, Martha A

Journal of lipid research

2007 Volume 49, Issue 1, Page(s) 98–106

Abstract: Conjugated linoleic acid (CLA) induces insulin resistance preceded by rapid depletion of the adipokines leptin and adiponectin, increased inflammation, and hepatic steatosis in mice. To determine the role of leptin in CLA-mediated insulin resistance and ... ...

Abstract	Conjugated linoleic acid (CLA) induces insulin resistance preceded by rapid depletion of the adipokines leptin and adiponectin, increased inflammation, and hepatic steatosis in mice. To determine the role of leptin in CLA-mediated insulin resistance and hepatic steatosis, recombinant leptin was coadministered with dietary CLA in ob/ob mice to control leptin levels and to, in effect, negate the leptin depletion effect of CLA. In a 2 x 2 factorial design, 6 week old male ob/ob mice were fed either a control diet or a diet supplemented with CLA and received daily intraperitoneal injections of either leptin or vehicle for 4 weeks. In the absence of leptin, CLA significantly depleted adiponectin and induced insulin resistance, but it did not increase hepatic triglyceride concentrations or adipose inflammation, marked by interleukin-6 and tumor necrosis factor-alpha mRNA expression. Insulin resistance, however, was accompanied by increased macrophage infiltration (F4/80 mRNA) in adipose tissue. In the presence of leptin, CLA depleted adiponectin but did not induce insulin resistance or macrophage infiltration. Despite this, CLA induced hepatic steatosis. In summary, CLA worsened insulin resistance without evidence of inflammation or hepatic steatosis in mice after 4 weeks. In the presence of leptin, CLA failed to worsen insulin resistance but induced hepatic steatosis in ob/ob mice.
MeSH term(s)	Adiponectin/blood ; Animals ; Body Weight ; Dietary Fats, Unsaturated/administration & dosage ; Fatty Liver/chemically induced ; Fatty Liver/metabolism ; Glucose/analysis ; Insulin/blood ; Insulin Resistance ; Interleukin-6/blood ; Leptin/administration & dosage ; Leptin/metabolism ; Linoleic Acids, Conjugated/administration & dosage ; Lipid Metabolism ; Macrophages/drug effects ; Male ; Mice ; Mice, Mutant Strains ; Mice, Obese ; Obesity/metabolism ; Recombinant Proteins/administration & dosage ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Adiponectin ; Dietary Fats, Unsaturated ; Insulin ; Interleukin-6 ; Leptin ; Linoleic Acids, Conjugated ; Recombinant Proteins ; Tumor Necrosis Factor-alpha ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2007-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M700195-JLR200
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Article: Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice.

Liu, Li-Fen / Purushotham, Aparna / Wendel, Angela A / Belury, Martha A

American journal of physiology. Gastrointestinal and liver physiology

2007 Volume 292, Issue 6, Page(s) G1671–82

Abstract: Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and ... ...

Abstract	Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of Rosi and CLA on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed male C57Bl/6 mice. CLA alone suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of Rosi attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase and fatty acid translocase (FAT/CD36) mRNA, suggesting inhibition of fatty acid uptake into adipose; addition of Rosi completely rescued this effect. In addition, CLA alone increased markers of macrophage infiltration, F4/80, and CD68 mRNA levels, without inducing TNF-alpha in epididymal adipose tissue. The ratio of Bax to Bcl2, a marker of apoptosis, was significantly increased in adipose of the CLA-alone group and was partially prevented by treatment of Rosi. Immunohistochemistry of F4/80 demonstrates a proinflammatory response induced by CLA in epididymal adipose. In the liver, CLA alone induced microsteatotic liver but surprisingly increased the rate of very-low-density lipoprotein-triglyceride production without inducing inflammatory mediator-TNF-alpha and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36, and fatty acid synthase. The combined administration of CLA and Rosi reduced hepatic liver triglyceride content as well as lipogenic gene expression compared with CLA alone. In summary, dietary CLA prevented weight gain in Rosi-treated mice without attenuating the beneficial effects of Rosi on insulin sensitivity. Rosi ameliorated CLA-induced lipodystrophic disorders that occurred in parallel with rescued expression of adipocytokine and adipocytes-abundant genes.
MeSH term(s)	Adipocytes/drug effects ; Adipocytes/metabolism ; Adiponectin/blood ; Adipose Tissue/drug effects ; Adipose Tissue/metabolism ; Adipose Tissue/pathology ; Adipose Tissue/physiopathology ; Adiposity/drug effects ; Animals ; Apoptosis/drug effects ; Body Weight/drug effects ; Dietary Fats ; Disease Models, Animal ; Drug Therapy, Combination ; Fatty Liver/chemically induced ; Fatty Liver/metabolism ; Fatty Liver/physiopathology ; Fatty Liver/prevention & control ; Hypoglycemic Agents/adverse effects ; Hypoglycemic Agents/pharmacology ; Insulin Resistance ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Leptin/blood ; Linoleic Acids, Conjugated/adverse effects ; Linoleic Acids, Conjugated/pharmacology ; Lipid Metabolism/drug effects ; Lipid Metabolism/genetics ; Lipoproteins, VLDL/metabolism ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver/physiopathology ; Macrophages/drug effects ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/drug therapy ; Obesity/etiology ; Obesity/metabolism ; Obesity/physiopathology ; RNA, Messenger/metabolism ; Thiazolidinediones/adverse effects ; Thiazolidinediones/pharmacology ; Time Factors ; Triglycerides/metabolism
Chemical Substances	Adiponectin ; Adipoq protein, mouse ; Dietary Fats ; Hypoglycemic Agents ; Intracellular Signaling Peptides and Proteins ; Leptin ; Linoleic Acids, Conjugated ; Lipoproteins, VLDL ; RNA, Messenger ; Thiazolidinediones ; Triglycerides ; very low density lipoprotein triglyceride ; rosiglitazone (05V02F2KDG)
Language	English
Publishing date	2007-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	603840-2
ISSN	1522-1547 ; 0193-1857
ISSN (online)	1522-1547
ISSN	0193-1857
DOI	10.1152/ajpgi.00523.2006
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Article ; Online: Hepatic deletion of SIRT1 decreases hepatocyte nuclear factor 1α/farnesoid X receptor signaling and induces formation of cholesterol gallstones in mice.

Purushotham, Aparna / Xu, Qing / Lu, Jing / Foley, Julie F / Yan, Xingjian / Kim, Dong-Hyun / Kemper, Jongsook Kim / Li, Xiaoling

Molecular and cellular biology

2012 Volume 32, Issue 7, Page(s) 1226–1236

Abstract: SIRT1, a highly conserved NAD(+)-dependent protein deacetylase, is a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although SIRT1 has been implicated in a number of hepatic metabolic processes, the mechanisms ... ...

Abstract	SIRT1, a highly conserved NAD(+)-dependent protein deacetylase, is a key metabolic sensor that directly links nutrient signals to animal metabolic homeostasis. Although SIRT1 has been implicated in a number of hepatic metabolic processes, the mechanisms by which hepatic SIRT1 modulates bile acid metabolism are still not well understood. Here we report that deletion of hepatic SIRT1 reduces the expression of farnesoid X receptor (FXR), a nuclear receptor that regulates bile acid homeostasis. We provide evidence that SIRT1 regulates the expression of FXR through hepatocyte nuclear factor 1α (HNF1α). SIRT1 deficiency in hepatocytes leads to decreased binding of HNF1α to the FXR promoter. Furthermore, we show that hepatocyte-specific deletion of SIRT1 leads to derangements in bile acid metabolism, predisposing the mice to development of cholesterol gallstones on a lithogenic diet. Taken together, our findings indicate that SIRT1 plays a vital role in the regulation of hepatic bile acid homeostasis through the HNF1α/FXR signaling pathway.
MeSH term(s)	Animals ; Cholesterol/metabolism ; Gallstones/metabolism ; Gene Deletion ; Gene Expression Regulation ; HEK293 Cells ; Hepatocyte Nuclear Factor 1-alpha/metabolism ; Humans ; Lipid Metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction ; Sirtuin 1/genetics ; Sirtuin 1/metabolism
Chemical Substances	Hepatocyte Nuclear Factor 1-alpha ; Receptors, Cytoplasmic and Nuclear ; farnesoid X-activated receptor (0C5V0MRU6P) ; Cholesterol (97C5T2UQ7J) ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-)
Language	English
Publishing date	2012-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.05988-11
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Article: Maintenance of adiponectin attenuates insulin resistance induced by dietary conjugated linoleic acid in mice.

Purushotham, Aparna / Wendel, Angela A / Liu, Li-Fen / Belury, Martha A

Journal of lipid research

2006 Volume 48, Issue 2, Page(s) 444–452

Abstract: Conjugated linoleic acid (CLA) causes insulin resistance and hepatic steatosis in conjunction with depletion of adipokines in some rodent models. Our objective was to determine whether the maintenance of adipokines, mainly leptin and adiponectin, by ... ...

Abstract	Conjugated linoleic acid (CLA) causes insulin resistance and hepatic steatosis in conjunction with depletion of adipokines in some rodent models. Our objective was to determine whether the maintenance of adipokines, mainly leptin and adiponectin, by either removing CLA from diets or using an adiponectin enhancer, rosiglitazone (ROSI), could attenuate CLA-induced insulin resistance. Male C57BL/6 mice were consecutively fed two experimental diets containing 1.5% CLA mixed isomer for 4 weeks followed by a diet without CLA for 4 weeks. CLA significantly depleted adiponectin but not leptin and was accompanied by hepatic steatosis and insulin resistance. These effects were attenuated after switching mice to the diet without CLA along with restoration of adiponectin. To further elucidate the role of adiponectin in CLA-mediated insulin resistance, ROSI was used in a subsequent study in male ob/ob mice fed either control (CON) or CLA diet. ROSI maintained significantly higher adiponectin levels in CON- and CLA-fed mice and prevented the depletion of epididymal adipose tissue and the development of insulin resistance. In conclusion, we show that insulin resistance induced by CLA may be related more to adiponectin depletion than to leptin and that maintaining adiponectin levels alone either by removing CLA or using ROSI can attenuate these effects.
MeSH term(s)	Adiponectin/metabolism ; Animals ; Body Weight ; Dietary Fats/pharmacology ; Disease Models, Animal ; Insulin Resistance/physiology ; Linoleic Acids, Conjugated/pharmacology ; Liver/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Organ Size
Chemical Substances	Adiponectin ; Dietary Fats ; Linoleic Acids, Conjugated
Language	English
Publishing date	2006-10-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.M600393-JLR200
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Zs.A 175: Show issues

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Article ; Online: Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation.

Purushotham, Aparna / Schug, Thaddeus T / Xu, Qing / Surapureddi, Sailesh / Guo, Xiumei / Li, Xiaoling

Cell metabolism

2008 Volume 9, Issue 4, Page(s) 327–338

Abstract: Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient ... ...

Abstract	Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD+-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPARalpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPARalpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPARalpha targets. SIRT1 interacts with PPARalpha and is required to activate PPARalpha coactivator PGC-1alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases.
MeSH term(s)	Animals ; Dietary Fats/administration & dosage ; Dietary Fats/pharmacology ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/pathology ; Fatty Acids/metabolism ; Fatty Liver/complications ; Fatty Liver/enzymology ; Feeding Behavior/drug effects ; Gene Deletion ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Homeostasis/drug effects ; Inflammation/complications ; Inflammation/enzymology ; Ligands ; Lipid Metabolism/drug effects ; Mice ; Organ Specificity/drug effects ; Oxidation-Reduction/drug effects ; PPAR alpha/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Protein Binding/drug effects ; Signal Transduction/drug effects ; Sirtuin 1 ; Sirtuins/genetics ; Sirtuins/metabolism ; Trans-Activators/metabolism ; Transcription Factors ; Transcriptional Activation/drug effects
Chemical Substances	Dietary Fats ; Fatty Acids ; Ligands ; PPAR alpha ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Ppargc1a protein, mouse ; Trans-Activators ; Transcription Factors ; Sirt1 protein, mouse (EC 3.5.1.-) ; Sirtuin 1 (EC 3.5.1.-) ; Sirtuins (EC 3.5.1.-)
Language	English
Publishing date	2008-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2009.02.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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