Metabolic responses to leptin in obese <i>db</i>/<i>db</i> mice are strain dependent

Harris, Ruth B. S.; Mitchell, Tiffany D.; Yan, Xiaolang; Simpson, Jacob; Redmann, Stephen M.

doi:10.1152/ajpregu.2001.281.1.r115

Cited by 55 publications

(39 citation statements)

References 43 publications

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“…Others have suggested that the short-form receptors act as transport proteins, facilitating passage of leptin into the brain (15). Recently we have shown that BL/6J db/db mice, which do not express the longform leptin receptor, are metabolically responsive to leptin administered peripherally (19), suggesting that short-form receptors have a function beyond that of a transport protein. It does not appear, however, that the failure of BL/3J db/db mice to accurately compensate for lipectomy as quickly as the other genotypes of mice in experiment 2 is due to either a decreased energy intake or an increased thermogenesis compared with BL/6J db/db mice, because food intakes and rectal temperatures are not different between genotypes (Harris, unpublished observations).…”

Section: Discussionmentioning

confidence: 91%

Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes

Harris

Hausman

Bartness

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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ob/ob mice; db/db mice; total body fat; cell size distribution THE NOTION THAT TOTAL BODY FAT is regulated has a long history in regulatory biology. Various feedback systems have been hypothesized to account for observations that lipid energy stores are regulated at levels appropriate for the internal and external environment of an animal. As early as 1953, Kennedy (23) proposed the "lipostatic hypothesis," suggesting that long-term energy balance is achieved by controlling lipid energy stores. Evidence often cited in support of a hypothetical total body fat regulatory system involves experimental modification of adiposity by fasting or overfeeding to decrease and increase body fat, respectively (31,38,39). These studies, however, may be confounded by responses associated with the energetic challenge, such as stress, changes in feeding behavior, and changes in activity of the autonomic nervous system, each of which has the potential to affect energy balance independently. Thus it is difficult to determine whether the metabolic and behavioral changes occur as a direct consequence of under-or overfeeding or are secondary to a change in body fat mass. One experimental challenge of the regulatory system that is more selective is surgical partial lipectomy (referred to hereafter as lipectomy). As we noted in a review of the literature recently (34), lipectomy immediately decreases total body fat, and because recovery from the surgery is rapid, changes in metabolism and behavior can be directly attributed to changes in adiposity. The literature on recovery of total body fat after lipectomy overwhelmingly supports an apparent regulation of adiposity levels in a variety of species, including laboratory rats and mice, Syrian and Siberian hamsters, and ground squirrels (for review, see Ref. 34).The mechanism by which total body fat levels are recovered after lipectomy is unknown. One obvious possibility is that leptin, a peptide hormone produced primarily, but not exclusively, by white fat (for review, see Ref. 1), serves as a feedback signal of the size of body lipid stores. Circulating leptin levels tend to reflect total body fat in human and nonhuman animals (10). Thus a decrease in circulating concentrations of leptin could potentially inform the brain of a loss of body fat and trigger compensatory responses such as increasing food intake and decreasing energy expenditure (9, 16). The importance of leptin as a signal of energy deficit is discussed elsewhere (2), but in the experiments described here we tested the hypothesis that leptin is part of a feedback system that regulates total body fat levels (7, 32).The specific purpose of the present experiment was to test whether leptin plays a critical role in the recovery of total body fat in mice that have experienced lipectomy-induced lipid deficits. This was accomplished by performing lipectomy in mice that exhibit genetically induced alterations in the production of leptin or of some of its receptor subtypes. The first experiment used ob/ob mice, which do not secrete ...

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Section: Discussionmentioning

confidence: 91%

Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes

Harris

Hausman

Bartness

2002

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Understanding the overall biological etiology of obesity will require 1973; Harris et al 2001;Hofmann et al 2001). That is, different alleles of genes other than the knockout or identification of genes responsible for each of these different mechanisms.…”

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confidence: 99%

Characterization of Epistasis Influencing Complex Spontaneous Obesity in the BSB Model

Diament

Chiu

et al. 2004

Genetics

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There is growing awareness that complex interactions among multiple genes and environmental factors play an important role in controlling obesity traits. The BSB mouse, which is produced by the backcross of (lean C57BL/6J ϫ lean Mus spretus) ϫ C57BL/6J, provides an excellent model of epistatic obesity. To evaluate potential epistatic interactions among six chromosomal regions previously determined to influence obesity phenotypes, we performed novel Bayesian analyses on the basis of both epistatic and nonepistatic models for four obesity traits: percentage of body fat, adiposity index, total fat mass, and body weight, and also for plasma total cholesterol. The epistatic analysis detected at least one more QTL than the nonepistatic analysis did for all obesity traits. These obesity traits were variously influenced by QTL on chromosomes 2, 7, 12, 15, and 16. Interaction between genes on chromosomes 2 and 12 was present for all obesity traits, accounting for 3-4.8% of the phenotypic variation. Chromosome 12 was found to have weak main effects on all obesity traits. Several different epistatic interactions were also detected for percentage of body fat, adiposity index, and total fat mass. Chromosomes 6 and 12 have not only main effects but also strong epistatic effects on plasma total cholesterol. Our results emphasize the importance of modeling epistasis for discovery of obesity genes.

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“…These epistatic interactions likely influence many complex diseases, with obesity as a clear example (17)(18)(19). Evidence that epistasis is common in obesity has been derived from statistical analyses (20), but it is also apparent from the almost universal observation that obesity phenotypes of knockout and spontaneous mutant mice are dependent on the background mouse strain on which the mutations are placed (21)(22)(23)(24). That is, different alleles of genes other than the knockout or mutant gene present in different mouse strains interact with (are epistatic with) the knockout or mutation to produce the phenotype.…”

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Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice

Chiu

Allison

et al. 2004

Journal of Lipid Research

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BSB mice exhibit a wide range of obesity despite being produced by a backcross of lean C57BL/6J (B) ؋ lean Mus spretus (SPRET/Pt) F1 animals ؋ B. Previous linkage studies identified a quantitative trait locus (QTL) on mouse chromosome 7 with coincident peaks for hepatic lipase activity, obesity, and plasma cholesterol. However, these mice were not analyzed for gene ؋ gene epistasis. Hepatic lipase activity is correlated with obesity and plasma cholesterol levels. In this study, we identified QTLs for plasma hepatic lipase activity with three statistical mapping methods: maximum likelihood interval mapping, Bayesian nonepistatic mapping, and Bayesian epistatic mapping. Bayesian epistatic mapping detected not only the QTL on chromosome 7 but also an additional QTL on chromosome 3, which has a weak main effect but a strong interaction with chromosome 7. SPRET/Pt alleles of the QTL on each chromosome promote hepatic lipase activity.The proportion of phenotypic variance explained by the epistatic effect is higher than that explained by the main effect of the QTL on chromosome 7. -Yi, N., S. Chiu, D. B. Allison, J. S. Fisler, and C. H. Warden. Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice.

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Metabolic responses to leptin in obese db/db mice are strain dependent

Cited by 55 publications

References 43 publications

Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes

Compensation for partial lipectomy in mice with genetic alterations of leptin and its receptor subtypes

Characterization of Epistasis Influencing Complex Spontaneous Obesity in the BSB Model

Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice

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