Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats

Scarpace, Philip J.; Matheny, Michael; Tümer, Nihal

doi:10.1016/s0306-4522(01)00142-7

Cited by 141 publications

(133 citation statements)

References 24 publications

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“…This, together with the fact that body weight and daily food intake are also higher in old than in young rats [7], suggest that old Wistar rats present leptin resistance. This agrees well with the data of other authors who described leptin resistance in other rodent models of ageing [12,13,18,23]. A decrease in the ratio CSF-to-serum leptin concentrations suggested that a failure at the level of the transport from blood to CSF could be the cause of leptin resistance in obese humans [8].…”

Section: Discussionsupporting

confidence: 92%

“…administration of leptin in old Fisher 344XBN rats have been described by others [24]. A decreased maximum response, rather than a decreased sensitivity has been reported after central administration of leptin in old Fisher 344XBN rats [13]. This discrepancy, apart from differences in the rat model, could rely on the methodological approaches used in each case: an in vitro assay such as STAT-3 phosphorylation after acute injections of leptin in Fisher 344XBN rats [13] versus in vivo responses under lower amounts of leptin chronically infused.…”

Section: Resultsmentioning

confidence: 65%

“…leptin administration with similar sensitivity as lean mice but did not respond to peripheral leptin administration. In old obese Fisher 344XBN rats, leptin resistance has been reported to occur at the central level [13,24] and to involve alterations in leptin signal transduction cascade [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…Alteration of leptin transport across the blood-brain barrier has been proposed to occur in obese humans [8,9], in New Zealand obese mice [10] and in diet-induced obese mice [11]. An impairment in the leptin signal transduction cascade has been shown in the old Fisher 344XBN rat [12,13].…”

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confidence: 99%

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Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

et al. 2002

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Aims/hypothesis. Ageing is associated with insulin and leptin resistance in mammals. These alterations might be caused by the increased adiposity associated with ageing, by ageing alone or both. We studied whether leptin resistance occurs at the central level in the Wistar rat and we aimed to discriminate between the effects of ageing from those of the increased adiposity associated with ageing. Methods. Leptin was infused intracerebroventricularly at a constant rate in young adult, old and old Wistar rats fasted for 3 months, using osmotic pumps. The effects on body weight, daily food intake, Lee index, adiposity and serum leptin values were analysed. The effect of food restriction on the expression of the long form of leptin receptor in the hypothalamus was also studied. Results. Leptin decreased daily food intake and body weight in young and old Wistar rats. With a dose of 10 µg/day similar responses were obtained in young and old rats but with a dose of 0.2 µg/day, only young rats showed decreases in these parameters. Foodrestriction in old rats lowered adiposity and serum leptin to values close to those of young rats, recovered responsiveness to i.c.v. administration of leptin at the dose of 0.2 µg/day and increased leptin receptor expression in the hypothalamus. Conclusion/interpretation. Our data show that old Wistar rats have a decreased response to leptin at the central level. Food-restriction recovers leptin responsiveness and increases leptin receptor in the hypothalamus suggesting that adiposity plays a key role in the development of leptin resistance associated with ageing. [Diabetologia (2002[Diabetologia ( ) 45:997-1003 Keywords Leptin, leptin-resistance, food-restriction, ageing, Wistar rat.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

et al. 2002

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“…Nuclear protein extracts were prepared immediately following removal of the hypothalamus as in our previous study [15]. At the time the animals were killed, hypothalami were homogenised with a glass pestle in 1 ml of 10 mmol/l HEPES, pH 7.9, 1.5 mmol/l MgCl 2 , 10 mmol/l KCl, 0.5 mmol/l dithiothreitol and 0.2 mmol/l phenylmethylsulphonyl fluoride (PMSF).…”

Section: Preparation Of Nuclear Protein Extractsmentioning

confidence: 99%

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

et al. 2005

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Aims/hypothesis: Leptin resistance is generally considered a consequence of obesity. We postulated that leptin resistance is associated with diminished hypothalamic leptin signalling capacity and that leptin resistance is causal to obesity. We assessed maximal leptin-mediated binding of the transcription factor signal transducer and activator of transcription 3 (STAT3), and the response to high-fat feeding in lean leptin-resistant rats. Materials and methods: Recombinant adeno-associated virus encoding rat leptin cDNA (rAAV-leptin) or control vector were administered by intracerebroventricular injection to lean F344×BN rats for up to 150 days, and food consumption, body weight, serum leptin and glucose tolerance were measured. Leptin-mediated hypothalamic transcription factor binding was assessed at day 150 following an intracerebroventricular injection of 2 μg leptin. Rats pretreated with either control or rAAV-leptin vector for 94 days were given a high-fat diet, and energy intake, body weight gain and adiposity were examined. Results: The rAAV-leptin-treated rats initially responded to leptin gene delivery then became leptin-resistant. They displayed persistent submaximal hypothalamic leptin signalling and enhanced insulin sensitivity, yet maximal hypothalamic signalling capacity was decreased by more than 50%. On a high-fat diet, the leptinresistant rats consumed more energy, gained more weight and accumulated greater visceral fat mass than controls. Conclusions/interpretation: The maximal hypothalamic leptin signalling capacity was diminished in leptin-resistant rats receiving central rAAV-leptin gene therapy. Moreover, this leptin-invoked leptin resistance perturbs the regulation of energy homeostasis in response to high fat exposure, producing augmented energy consumption. This, coupled with potential hypersensitivity to insulin, creates a milieu favouring fat deposition. Our data suggest that leptin resistance is both a consequence and cause of obesity.

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Impact of Leptin on Ovarian Folliculogenesis and Assisted Reproduction

Brannian

Hansen

2003

Leptin and Reproduction

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Hypothalamic leptin resistance is associated with impaired leptin signal transduction in aged obese rats

Cited by 141 publications

References 24 publications

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

Leptin resistance exacerbates diet-induced obesity and is associated with diminished maximal leptin signalling capacity in rats

Impact of Leptin on Ovarian Folliculogenesis and Assisted Reproduction

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