Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.

Considine, Robert V.; Considine, Eileen L.; Williams, Charlene J.; Nyce, Mark R.; Magosin, Susan; Bauer, Thomas; Rosato, Ernest L.; Colberg, James E.; José, F.

doi:10.1172/jci118007

Cited by 354 publications

(244 citation statements)

References 10 publications

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“…Leptin causes weight loss in mice by reducing food intake and increasing energy expenditure (2)(3)(4)(5). Furthermore, ob gene expression is increased in human obesity (6)(7)(8)(9) and in various animal models of obesity (10). The accumulated evidence suggests that leptin is important in controlling body weight.…”

mentioning

confidence: 99%

Role of leptin in hypothalamic–pituitary function

Kimura²,

Walczewska³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

663

439

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A defect in the structure of the obese gene is responsible for development of obesity in the ob͞ob mouse. The product of expression of the gene is the protein hormone leptin. Leptin causes weight loss in ob͞ob and normal mice, it is secreted by adipocytes, and it is an important controller of the size of fat stores by inhibiting appetite. The ob͞ob mouse is infertile and has a pattern of gonadotropin secretion similar to that of prepubertal animals. Consequently, we hypothesized that leptin might play a role in the control of gonadotropin secretion and initiated studies on its possible acute effects on hypothalamic-pituitary function. After a preincubation period, hemi-anterior pituitaries of adult male rats were incubated with leptin for 3 hr. Leptin produced a dose-related increase in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) release, which reached peaks with 10 ؊9 and 10 ؊11 M leptin, respectively. Gonadotropin release decreased at higher concentrations of leptin to values indistinguishable from that of control pituitaries. On the other hand, prolactin secretion was greatly increased in a dose-related manner but only with leptin concentrations (10 ؊7 -10 ؊5 M). Incubation with leptin of median eminence-arcuate nuclear explants from the same animals produced significant increases in LH-releasing hormone (LHRH) release only at the lowest concentrations tested (10 ؊12 -10 ؊10 M). As the leptin concentration was increased, LHRH release decreased and was significantly less than control release at the highest concentration tested (10 ؊6 M). To determine if leptin can also release gonadotropins in vivo, ovariectomized females bearing implanted third ventricle cannulae were injected with 10 g of estradiol benzoate s.c., followed 72 hr later by microinjection into the third ventricle of leptin (0.6 nmol in 5 l) or an equal volume of diluent. There was a highly significant increase in plasma LH, which peaked 10-50 min after injection of leptin. Leptin had no effect on plasma FSH concentrations, and the diluent had no effect on either plasma FSH or LH. Thus, leptin at very low concentrations stimulated LHRH release from hypothalamic explants and FSH and LH release from anterior pituitaries of adult male rats in vitro and released LH, but not FSH, in vivo. The results indicate that leptin plays an important role in controlling gonadotropin secretion by stimulatory hypothalamic and pituitary actions.

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mentioning

confidence: 99%

Role of leptin in hypothalamic–pituitary function

Kimura²,

Walczewska³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

663

439

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“…Whereas some progress in treatment of these children with leptin has been reported, treatment of obese subjects without mutations the leptin gene has been less successful. Obese humans actually have elevated rather than decreased levels of leptin suggestive of hormonal resistance analogous to insulin resistance (50) and leptin levels show a strong positive correlation with the total fat mass (51). Moreover, contribution of common variants in the leptin receptor gene to obesity and obesity-related phenotypes including leptin levels has remained more or less elusive.…”

Section: Obesity Genes and Type 2 Diabetesmentioning

confidence: 99%

Genetic dissection of type 2 diabetes

Ridderstråle¹,

Groop²

2009

Molecular and Cellular Endocrinology

122

114

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Compared to the successful probing of genetic causes of monogenic disorders, dissecting the genetics of complex polygenic diseases has until recently been a fairly slow and cumbersome process. With the introduction of whole genome wide association studies (WGAS) the situation dramatically changed in 2007. The results from several recent WGAS on type 2 diabetes (T2D) and obesity have identified at least eighteen genes consistently associated with T2D. Many of the genes implicate pancreatic beta-cell function in the pathogenesis of T2D whereas only one clearly associate with insulin resistance. The identified genes most likely merely represent the tip of the iceberg in the explanation behind T2D. Refined tools will have to provide a more complete picture of the genetic complexity of T2D over the next few years. In addition to common variants increasing susceptibility for the disease, rare variants with stronger effects, copy number variations, and epigenetic effects like DNA methylation and histone acetylation will become important. Nevertheless, today we are able for the first time to anticipate that the genetics of a complex disease like T2D really can be dissected. Key wordsgenetics, complex disease, monogenic, polygenic, linkage study, genome wide scan, association study, single nucleotide polymorphism, epigenetic, type 2 diabetes, obesity. Evidence that type 2 diabetes is inheritedThere is ample evidence that T2D has a strong genetic component. The concordance of T2D in monozygotic twins is approximately 70% compared with 20-30% in dizygotic twins (1,2). Given the age-dependent penetrance of the disease, it is clear that the longer the follow-up, the higher the concordance rate (2). T2D clusters in families. The life-time risk of developing the disease is about 40% in offspring of one parent with T2D (3), greater if the mother is affected (4), the risk approaching 70% if both parents have diabetes. Translated into a s-value, the recurrence risk for a sibling of an affected person divided by the risk for the general population, this means that a first-degree relative of a patient with type 2 diabetes has a 3-fold increased risk of developing the disease (5). Large ethnic differences in the prevalence of T2D have also been ascribed to a genetic component (6,7). The change in the environment towards a more affluent Western life style plays a key role in the epidemic increase in the prevalence of T2Dworldwide. This change has occurred during the last 50 years. Clearly, our genes have not changed during this period but this does not exclude an important role for genes in the rapid increase in T2D, since genes or gene variants explain how we respond to the environment. Page 4 of 25A c c e p t e d M a n u s c r i p t 4 Thrifty genotypes or phenotypes?A plausible explanation for the interaction between genes and environment comes from the thrifty gene hypothesis. Neel (8) proposed that individuals living in an environment with unstable food supply (as for hunters and nomads) would maximize their probabilit...

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“…The ob gene has recently been cloned and shown to encode for a 167-amino acid protein, leptin, which is secreted exclusively from the adipocytes of white fat [1][2][3][4][5]. Leptin has been shown to lower body weight by restraining appetite [5][6][7][8] and by altering metabolic processes [6].…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, leptin mRNA levels have been studied in rats with obesity secondary to ventromedial hypothalamic lesions and increase in parallel with body weight [10,11], fulfilling one of the requirement of this regulatory system. Also in humans, it has recently been shown that leptin mRNA levels in white adipocytes increase or decrease in parallel with the body mass index [3,12]. Although believed to be a long-term regulator of body weight, increasing *Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Regulation of ob gene mRNA levels in cultured adipocytes

1996

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mRNA levels of the ob gene product, leptin, were investigated by quantitative competitive RT-PCR in a mouse cell line (3T3-L1) which can be induced to differentiate into adipocytes. During conversion to fat cells, the level of leptin mRNA increased several-fold and in parallel to that for typical adipocyte markers like lipoprotein lipase, adipsin and glycerophosphate dehydrogenase. Leptin transcription, however, did not correlate with the size of the adipocytes measured as total triglycerides. On the other hand, mRNA levels for leptin in fully differentiated adipocytes were increased 2-3 fold by insulin. In contrast, free fatty acids exerted a concentration-dependent inhibition of leptin transcription while the corticosteroid dexamethasone and an elevation of intracellular cAMP displayed only marginal inhibitory effects on leptin mRNA levels.

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Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity.

Cited by 354 publications

References 10 publications

Role of leptin in hypothalamic–pituitary function

Role of leptin in hypothalamic–pituitary function

Genetic dissection of type 2 diabetes

Regulation of ob gene mRNA levels in cultured adipocytes

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