Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: Developmental aspects

Moran, Timothy H.; Bi, Sheng

doi:10.1002/dev.20149

Cited by 61 publications

(66 citation statements)

References 36 publications

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“…The biochemical and histopathological alterations observed in adult OLETF rats during obesity and steatosis are similar to the hepatic fatty degeneration present in obese individuals (24). OLETF rats have a deletion in the gene encoding cholecystokinin (CCK)-1 receptor, making the OLETF rat a CCK-1 receptor knockout model (25). CCK, the brain-gut peptide, inhibits food intake by reducing the size and duration of a meal, and its inhibitory actions are mediated through CCK-1 receptors.…”

Section: Binge Alcohol Consumption Aggravates Oxidative Stress and Prmentioning

confidence: 83%

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

Minato

Tsutsumi

Tsuchishima

et al. 2014

Mol Med

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The pathogenesis of nonalcoholic steatohepatitis (NASH) is a two-stage process in which steatosis is the "first hit" and an unknown "second hit." We hypothesized that "a binge" could be a "second hit" to develop NASH from obesity-induced simple steatosis. Thirty-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were administered 10 mL of 10% ethanol orally for 5, 3, 2, and 1 d/wk for 3 consecutive weeks. As control, male Otsuka Long-Evans Tokushima (OLET) rats were administered the same amount of alcohol. Various biochemical parameters of obesity, steatosis and NASH were monitored in serum and liver specimens in untreated and ethanol-treated rats. The liver sections were evaluated for histopathological alterations of NASH and stained for cytochrome P-4502E1 (CYP2E1) and 4-hydroxy-nonenal (4-HNE). Simple steatosis, hyperinsulinemia, hyperglycemia, insulin resistance, hypertriglycemia and marked increases in hepatic CYP2E1 and 4-HNE were present in 30-wk-old untreated OLETF rats. Massive steatohepatitis with hepatocyte ballooning was observed in the livers of all OLETF rats treated with ethanol. Serum and hepatic triglyceride levels as well as tumor necrosis factor (TNF)-α mRNA were markedly increased in all ethanol-treated OLETF rats. Staining for CYP2E1 and 4-NHE demonstrated marked increases in the hepatic tissue of all the groups of OLETF rats treated with ethanol compared with OLET rats. Our data demonstrated that "a binge" serves as a "second hit" for development of NASH from obesity-induced simple steatosis through aggravation of oxidative stress. The enhanced levels of CYP2E1 and increased oxidative stress in obesity play a significant role in this process.

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Section: Binge Alcohol Consumption Aggravates Oxidative Stress and Prmentioning

confidence: 83%

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

Minato

Tsutsumi

Tsuchishima

et al. 2014

Mol Med

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“…Studies in animal models disagree with respect to the causal factor. OLETF rats have a deficiency in their saiety signaling, causing hyperphagia and obesity (92), which manifest in the pathological condition of steatosis by 20 weeks of age (109,110). Importantly, the emergence of this pathology is associated with mitochondrial dysfunction, with hepatic triglyceride accumulation preceding hepatic insulin resistance merely through the hyperphagic phenotype FIG.…”

Section: Mitochondria In Nafldmentioning

confidence: 99%

Mitochondrial Morphology in Metabolic Diseases

Galloway

Yoon

2013

Antioxidants & Redox Signaling

118

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Significance: Mitochondria are the cellular energy-producing organelles and are at the crossroad of determining cell life and death. As such, the function of mitochondria has been intensely studied in metabolic disorders, including diabetes and associated maladies commonly grouped under all-inclusive pathological condition of metabolic syndrome. More recently, the altered metabolic profiles and function of mitochondria in these ailments have been correlated with their aberrant morphologies. This review describes an overview of mitochondrial fission and fusion machineries, and discusses implications of mitochondrial morphology and function in these metabolic maladies. Recent Advances: Mitochondria undergo frequent morphological changes, altering the mitochondrial network organization in response to environmental cues, termed mitochondrial dynamics. Mitochondrial fission and fusion mediate morphological plasticity of mitochondria and are controlled by membrane-remodeling mechanochemical enzymes and accessory proteins. Growing evidence suggests that mitochondrial dynamics play an important role in diabetes establishment and progression as well as associated ailments, including, but not limited to, metabolism-secretion coupling in the pancreas, nonalcoholic fatty liver disease progression, and diabetic cardiomyopathy. Critical Issues: While mitochondrial dynamics are intimately associated with mitochondrial bioenergetics, their cause-and-effect correlation remains undefined in metabolic diseases. Future Directions: The involvement of mitochondrial dynamics in metabolic diseases is in its relatively early stages. Elucidating the role of mitochondrial dynamics in pathological metabolic conditions will aid in defining the intricate form-function correlation of mitochondria in metabolic pathologies and should provide not only important clues to metabolic disease progression, but also new therapeutic targets. Antioxid. Redox Signal. 19,[415][416][417][418][419][420][421][422][423][424][425][426][427][428][429][430]

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“…The size of spontaneous meals is almost double that of the lean background strain, the Long Evans Tokushima Otsuka (LETO) rats. Furthermore, OLETF rats have deficits in responding to CCK, and gastric and intestinal preloads [16,32]. The underlying cause(s) of hyperphagia in this rat model has not been fully understood.…”

Section: Introductionmentioning

confidence: 99%

Altered dopamine D2 receptor function and binding in obese OLETF rat

Hajnal

Margas

Covașă

2008

Brain Research Bulletin

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A decrease in D2 -like receptor (D2R) binding in the striatum has been reported in obese individuals and drug addicts. Although natural and drug rewards share neural substrates, it is not clear whether such effects contribute also to overeating on palatable meals as an antecedent of dietary obesity. Therefore, we investigated receptor density and the effect of the D2R agonist quinpirole (0.05, 0.5 mg/kg, S.C.) on locomotor activity and sucrose intake in a rat model of diet-induced obesity, the CCK-1 receptor-deficient Otsuka Long Evans Tokushima Fatty (OLETF) rat. Compared to agematched lean controls (LETO), OLETF rats expressed significantly lower [125I]-iodosulpride binding in the accumbens shell (−16%, p<0.02). Whereas the high dose of quinpirole increased motor activity in both strains equally, the low dose reduced activity more in OLETF. Both doses significantly reduced sucrose intake in OLETF but not LETO. These findings demonstrate an altered D2R signaling in obese OLETF rats similar to drug-induced sensitization and suggest a link between this effect and avidity for sucrose in this model.

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Hyperphagia and obesity of OLETF rats lacking CCK1 receptors: Developmental aspects

Cited by 61 publications

References 36 publications

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

Binge Alcohol Consumption Aggravates Oxidative Stress and Promotes Pathogenesis of NASH from Obesity-Induced Simple Steatosis

Mitochondrial Morphology in Metabolic Diseases

Altered dopamine D2 receptor function and binding in obese OLETF rat

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