Substitution at Codon 269 (Glutamine → Proline) of the Leptin Receptor (OB-R) cDNA Is the Only Mutation Found in the Zucker Fatty (fa/fa) Rat

Iida, Mitsuru; Murakami, Takashi; Ishida, Kaori; Mizuno, Akira; Kuwajima, Masamichi; Shima, Kenji

doi:10.1006/bbrc.1996.1070

Cited by 175 publications

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“…Obese homozygous (fa/fa) ZDF-Drt rats, which are unresponsive to leptin because of a loss-of-function mutation in their leptin receptor (10,11), and lean wild-type (ϩ/ϩ) ZDF controls were bred in our laboratory from ZDF/Drt-fa (F10) rats purchased from Dr. R. Peterson (University of Indiana School of Medicine, Indianapolis, IN). Two groups of mice, C57BL/6J-ob/ob and C57BL/KS-J-db/db, and their wild-type controls, C57BL/6J ϩ/ϩ and C57BL/KS-J ϩ/ϩ mice, were purchased from the Jackson Laboratory (Bar Harbor, ME).…”

Section: Methodsmentioning

confidence: 99%

“…In the absence of leptin action, lipogenesis is increased and fatty-acid (FA) oxidation is reduced (7), accounting for the steatosis and lipotoxicity that occur in such circumstances (7)(8)(9). For example, in Zucker Diabetic Fatty (ZDF) rats with a loss-of-function mutation in the leptin receptors (10,11), tissue TG ranges from 10 to 50 times the normal content (8) and is associated with functional impairment of pancreatic ␤-cells (12,13) and myocardium (9) and insulin resistance (14). Ultimately, the progressive overaccumulation of lipids causes death of cells in pancreatic islets and myocardium, resulting in diabetes and myocardial failure, which are the most serious complications of obesity.…”

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confidence: 99%

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Liporegulation in Diet-induced Obesity

Lee

Wang

Kakuma

et al. 2001

Journal of Biological Chemistry

241

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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 ϳ150-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 ␣ 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-␣ or oxidative enzymes, whereas lipogenesis from [ 14 C]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 fattyacid oxidation.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Liporegulation in Diet-induced Obesity

Lee

Wang

Kakuma

et al. 2001

Journal of Biological Chemistry

241

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“…The lipopenic effect of leptin is not observed in the Zucker Diabetic Fatty (ZDF) rat, because of a loss-offunction mutation in the leptin receptor, OB-R [29,30]. These abnormalities in the ZDF rat are prevented by treatment with the thiazolidinedione troglitazone [10] or severe caloric restriction [11], both of which we have found to activate AMPK in rat tissues [31,32].…”

Section: Introductionmentioning

confidence: 94%

“…The triglyceride accumulation is the result of a loss-of-function mutation in the leptin receptor [29,30], which deprives all tissues of the antisteatotic action of leptin. If the antisteatotic action of leptin is mediated by activated AMP kinase, then AICAR therapy should mimic the action of leptin and reduce the triglyceride content in tissues of leptin-resistant animals.…”

Section: Effect Of Aicar On Non-adipose Tissue Triglyceridesmentioning

confidence: 99%

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

et al. 2004

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Aims/hypothesis. Leptin has been shown to activate AMP-activated protein kinase (AMPK), an enzyme that regulates the activities of key enzymes of lipid synthesis and metabolism. We assess here (i) whether AMPK activity is diminished in rodents deficient in leptin or the leptin receptor, and (ii) the effects of treating the diabetes-prone, leptin-receptor-deficient Zucker Diabetic Fatty (ZDF) rat with an AMPK activator. Methods. AMPK activity and related parameters were measured in muscle and or liver of fa/fa and ZDF rats and ob/ob mice. We also explored the effect of treatment with the AMPK activator 5-aminoimidazole 4-carboxamide 1-β-D ribofuranoside (AICAR) (7.4 mmol/l, on Monday, Wednesday and Friday for 15 weeks, beginning at 7 weeks of age) on the phenotype of the ZDF rat. Results. AMPK activity was diminished in muscle and/or liver of fa/fa (leptin-receptor-deficient, non-diabetic) and ZDF (leptin-receptor-deficient, diabetesprone) rats and ob/ob mice (leptin-deficient). ZDF rats that had free access to food became hyperglycaemic (22.2 mmol/l) and hyperphagic after 2 to 5 weeks and remained so during the remainder of the study. Treatment of ZDF rats with AICAR prevented the development of diabetes, as well as increases of triglyceride content in liver, muscle and the pancreatic islets. It also attenuated the morphological abnormalities observed in the islets of untreated rats. Rats diet-matched with the AICAR-treated animals developed diabetes of intermediate severity and showed decreases in triglyceride content in the islets, but not in liver or muscle. Conclusions/interpretation. The results indicate that a deficiency of leptin or the leptin receptor is associated with a decrease in AMPK activity in muscle and/or liver. They also suggest that treatment with an AMPK activator prevents the development of diabetes and ectopic lipid accumulation in the ZDF rat.

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“…into free-feeding rats, at the beginning of the light phase, when these animals normally do not eat. In these studies, rats treated with the anti-leptin antibodies increased their food intake for more than 24 h. In contrast, obese Zucker faafa rats, expressing a defective ObRb receptor, 20,21 were unresponsive to central antibody administration. These observations suggest, that in fed rats, endogenous leptin plays a physiologically important role to suppress food intake.…”

Section: Introductionmentioning

confidence: 99%

A peptide leptin antagonist reduces food intake in rodents

et al. 1999

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OBJECTIVE: The purpose of the present study was to investigate the continuing validity of the hypothesis that leptin is a physiologically important regulator of food intake, using the human leptin mutant R128Q leptin. DESIGN: In a cellular proliferation assay, based on BAF-3 cells transfected with the murine ObRb receptor, R128Q leptin was shown to be devoid of agonistic activity and to competitively inhibit the proliferative effects of leptin. To determine whether R128Q leptin was also an antagonist of leptin in vivo, the leptin mutant was injected intracerebroventricularly (i.c.v.) into rats in the absence and presence of leptin. R128Q was also injected intraperitoneally (i.p.) into oba aob and into dba adb mice expressing, respectively, either normal or defective ObRb receptors. RESULTS: R128Q was shown to be a competitive antagonist of leptin induced cellular proliferation in vitro. Surprisingly, in vivo R128Q leptin produced a strong dose-dependent decrease in food intake, and was only slightly less potent than leptin itself. In fasted rats, the inhibitory effects of leptin and R128Q leptin (i.c.v.) on post-fast refeeding were additive. Finally, R128Q leptin produced the same inhibition of food intake as leptin when injected i.p. in oba aob mice and, like leptin, was inactive after i.p. injection to dba adb mice. CONCLUSION: R128Q leptin is a leptin agonist in vivo, but behaves as an antagonist against leptin induced proliferation in vitro. The data demonstrate that the human leptin mutant R128Q leptin is not a suitable tool for investigating the physiological actions of leptin.

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Substitution at Codon 269 (Glutamine → Proline) of the Leptin Receptor (OB-R) cDNA Is the Only Mutation Found in the Zucker Fatty (fa/fa) Rat

Cited by 175 publications

References 0 publications

Liporegulation in Diet-induced Obesity

Liporegulation in Diet-induced Obesity

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

A peptide leptin antagonist reduces food intake in rodents

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