Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat

Takaya, Kazuhiko; Ogawa, Yoshihiro; Hiraoka, Junko; Hosoda, Kiminori; Yamori, Yukio; Nakao, Kazuwa; Koletsky, Richard J.

doi:10.1038/ng1096-130

Cited by 192 publications

(107 citation statements)

References 19 publications

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“…The obese phenotype of the Koletsky rat also appears to be due to a defect in OB-R (44). In this case, a codon for an extracellular domain amino acid (common to all OB-R isoforms) has been mutated to a stop codon.…”

Section: Minireview: the Leptin Receptormentioning

confidence: 99%

The Leptin Receptor

Tartaglia

1997

Journal of Biological Chemistry

1,214

878

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Section: Minireview: the Leptin Receptormentioning

confidence: 99%

The Leptin Receptor

Tartaglia

1997

Journal of Biological Chemistry

1,214

878

View full text Add to dashboard Cite

“…However, it is certainly conceivable that one or more of the short receptor isoforms may mediate leptin actions in the periphery through presently unknown mechanisms. Notably, the obese phenotype of both the fa/fa Zucker rats [68,69] and the Koletsky rats [70,71] results from mutations that equally affect all leptin receptor isoforms. Specifically, fa/fa rats possess a missense mutation in the common extracellular domain of the leptin receptor [68,69], whereas Koletsky rats have a nonsense mutation that is predicted to lead to total absence of all leptin receptor isoforms [70,71].…”

Section: Leptin: From Gene To Protein and Beyondmentioning

confidence: 99%

Leptin: its role in obesity and beyond

1997

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The discovery of leptin, the product of the ob gene [1], has broadened the horizons of research in the regulation of body adiposity and energy balance. This hormone, produced exclusively by the adipose tissue, conveys to the brain information on the size of energy stores and activates hypothalamic centers that regulate energy intake and expenditure [2]. In addition, leptin affects several neuroendocrine mechanisms and regulates multiple hypothalamic-pituitary axes [2]. The realization that the adipose tissue is not merely a storage depot, but also an important endocrine gland, has revived the interest in the ªlipostatic theoryº of body fat regulation [3] and has opened new opportunities in the investigation and treatment of disorders such as obesity and anorexia nervosa.In this review, both the biology of leptin secretion and regulation as well as our progress in elucidating the role of leptin in various physiologic and pathophysiologic states are discussed. More specifically, particular emphasis is placed on our current thinking for the role of leptin in physiologic processes, such as control of body adiposity, adaptation to starvation and the onset of puberty as well as the pathogenesis of disorders such as obesity and anorexia nervosa. Finally, some of the important unanswered questions about leptin physiology are discussed and future directions for leptin research are suggested. Historic backgroundKennedy [3] first introduced the lipostatic theory of body weight control, according to which the adipose tissue produces a hormone that regulates body size. The elegant work of Hervey [4], based on parabiosis experiments using rats with hypothalamic lesions, suggested almost four decades ago the existence of such a factor that might act on the hypothalamus. Further work by Hausberger [5], and later by Coleman and Hummel [6], also employing the parabiosis paradigm between genetically obese and wild type animals, confirmed and extended Hervey's observations. In these studies, the circulatory systems of two animals were connected, allowing exchange of circulating hormones. Using genetically obese mice, such as the ob/ob and the db/db mice, in parabiosis with wild type animals, these investigators postulated the existence of a circulating factor in the wild type mice. They proposed that this substance was absent in ob/ob mice, since ob/ob mice would lose weight when connected to wild type mice. Furthermore, they speculated that db/db mice were resistant to the action of the unknown factor, since, on one hand, db/db mice in parabiosis with wild type animals fail to lose weight, and, on the other, wild type mice connected to db/db mice die of starvation. These findings were interpreted to result from the actions of large amounts of the unknown factor that was appropriately overproduced in response to tissue resistance in db/ db mice.All these predictions turned out to be correct when the ob gene was identified by positional cloning using the ob/ob animal model of obesity [1]. Thus, ob/ ob animals are obese because they ...

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“…Spontaneously hypertensive (SHR/NDmcr-cp) rats with a genetic mutation in the leptin receptor gene 18 exhibit a variety of metabolic abnormalities, including hypertension, obesity, glucose intolerance, hyperinsulinemia and dyslipidemia. Therefore, these rats are widely accepted as an experimental model for studies on MS. Otsuka Long Evans Tokushima Fatty (OLETF) rats and Goto-kakizaki (GK) rats have been used as a model for type II diabetes mellitus, whereas SHR/ NDmcr-cp rats are associated with a more prominent accumulation of visceral fat and are therefore considered to be a better model for advanced MS.…”

Section: Introductionmentioning

confidence: 99%

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

et al. 2009

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Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg À1 per day, p.o.) or ARB (olmesartan, 5 mg kg À1 per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-b mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

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Nonsense mutation of leptin receptor in the obese spontaneously hypertensive Koletsky rat

Cited by 192 publications

References 19 publications

The Leptin Receptor

The Leptin Receptor

Leptin: its role in obesity and beyond

Renoprotective effects of an angiotensin II receptor blocker in experimental model rats with hypertension and metabolic disorders

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