| Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions. | |
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MedLine Citation:
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PMID: 21382979 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipocyte differentiation, and an adipogenesis-promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho-knockout mice (11.7±0.3 g at 9 wk), leptin-deficient (ob/ob) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity [ob/ob-klotho double-knockout (DKO) mice]. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild-type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob-klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob-klotho DKO mice had significantly (P<0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob-klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob-klotho DKO mice, compared to their ob/ob counterparts (ob/ob vs. ob/ob-klotho DKO: 266 ± 36 vs. 65±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high-fat-diet-induced obesity, we provided a high-fat (60%) diet to klotho-knockout mice and compared them with normal-fat (20%) diet-fed klotho-knockout mice. No significant difference in body weight was detected in klotho-knockout mice fed either the normal-fat diet or high-fat diet, while WT mice fed the high-fat diet gradually gained body weight, compared to the normal-fat-diet-fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications. |
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Authors:
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Mutsuko Ohnishi; Shigeko Kato; Junko Akiyoshi; Azeddine Atfi; M Shawkat Razzaque |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-03-07 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 25 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-05-30 Completed Date: 2011-08-18 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 2031-9 Citation Subset: IM |
Affiliation:
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Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Research and Education Bldg., 190 Longwood Ave., Boston, MA 02115, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipose Tissue
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metabolism Animals Blood Glucose / genetics*, metabolism* Cholesterol / blood Diet* Dietary Fats Fatty Liver / metabolism, pathology Gene Expression Glucose / metabolism* Glucuronidase / antagonists & inhibitors*, genetics, metabolism Leptin / genetics, metabolism Liver / chemistry, metabolism Longevity Mice Mice, Knockout Obesity / genetics*, prevention & control PPAR gamma / metabolism Triglycerides / blood Weight Gain |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK077276-04/DK/NIDDK NIH HHS; R01-DK077276/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Blood Glucose; 0/Dietary Fats; 0/Leptin; 0/PPAR gamma; 0/Triglycerides; 50-99-7/Glucose; 57-88-5/Cholesterol; EC 3.2.1.31/Glucuronidase; EC 3.2.1.31/klotho protein |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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