Differential and genetically separable associations of leptin with obesity-related traits

Thorburn, Anne W.; Holdsworth, A; Proietto, Joseph; Morahan, Grant

doi:10.1038/sj.ijo.0801213

Cited by 17 publications

(9 citation statements)

References 39 publications

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“…Diabetes frequencies vary among the various NZO substrains. The NZO/Wehi stock develops comparable obesity as observed in NZO/Hl and NZO/HlLt mice (15); however, only males of the latter two strains develop chronic nonfasting hyperglycemia. Approximately, 50% of group-caged virgin NZO/Hl and NZO/HlLt males, but not females, transit from impaired glucose tolerance (IGT) into overt type 2 diabetes between 12 and 20 weeks of age when maintained on a diet containing 4.5% fat (16).…”

Section: The Nzo/hllt Mousementioning

confidence: 94%

Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

Leiter

Reifsnyder

2004

Diabetes

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The genetic basis for the more common forms of human obesity predisposing to insulin resistance and development of type 2 diabetes is multigenic rather than monogenic in origin. New mouse "diabesity" models have been created by combining independent diabetes riskconferring quantitative trait loci from two unrelated parental strains: New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/Lt). F1 hybrid males, heterozygous at all polymorphic autosomal loci distinguishing the two parental strains, are driven to obesityinduced diabetes (diabesity) at high frequencies. This review focuses on two new recombinant congenic strains (RCSs) developed by introgressing multiple NZO/HlLt chromosomal segments into the nominally diabesity-resistant NON/Lt strain background. Both RCSs gain more weight than NON animals. Although exhibiting comparable weight gain and adiposity, only one of the two RCSs develops diabetes. Hence, these two RCSs will be instructive in elucidating genetic and pathophysiological differences underlying uncomplicated obesity syndromes versus diabetogenic obesity (diabesity) syndromes. Unlike mice with null mutations in a single gene producing morbid obesity, the new models develop a more moderate obesity produced by the interaction of numerous genes with relatively small effects. These RCSs are differentially sensitive to adverse side effects of thiazolidinediones and thus should be particularly useful for pharmacogenetic analyses. Diabetes 53 (Suppl. 1):S4 -S11, 2004 G enetic architecture is a term used to describe the full range of genetic effects on a phenotype. This architecture is not a fixed entity but changes according to age-and sex-mediated shifts in gene expression, as well as changes in the physical environment. Most common forms of type 2 diabetes entail a complex interaction between multiple genes and the nutritional environment. Obesity represents a major phenotypic risk factor for type 2 diabetes susceptibility. Subphenotypic components of human obesity, such as body weight (BW) and percent fat, are continuously varying traits reflecting contributions from numerous quantitative trait loci (QTL) (1). Geneticists are currently grappling with the molecular genetic basis for variation in a complex phenotypic trait such as obesity that confers type 2 diabetes susceptibility (2). This effort requires development of new computational frameworks to enhance power to detect gene-gene interactions in genome-wide screens (3). However, understanding how these genomic interactions translate into dysregulated metabolic pathways (physiogenomics) is still difficult in humans. Currently, mutant stocks with defects in the leptin receptor or leptin genes (Lepr db and Lep ob mice) represent the most intensively studied mouse models of obesity-associated type 2 diabetes ("diabesity"). Although these mutant stocks are very useful, the genetic basis for their morbid obesity, as well as the pathophysiological basis for their insulin resistance, is not reflective of what is sometimes referred to as "garden-vari...

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Section: The Nzo/hllt Mousementioning

confidence: 94%

Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

Leiter

Reifsnyder

2004

Diabetes

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“…More evidence for a genetic link comes from defects in a polygenic mouse model of obesity (New Zealand Obese) where a 72% decrease in physical activity was seen prior to the gain in body fat mass (Thorburn et al, 2000). Additionally, mutations in the larval foraging gene is associated with reduce locomotory behavior in adulthood (Pereira and Sokolowski, 1993).…”

Section: Total Energy Expenditure and Agingmentioning

confidence: 99%

Energy expenditure and aging

Manini

2010

Ageing Research Reviews

222

143

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The study of energy expenditure (EE) has deep roots in understanding aging and lifespan in all species. In humans, total EE decreases substantially in advanced age resulting from parallel changes in resting metabolic rate (RMR) and activity EE. For RMR, this reduction appears to be due to a reduction in organ mass and specific metabolic rates of individual tissues. However, these anatomical changes explain very little regarding the decline in activity EE, which is governed by both genetic and environmental sources. The biological control centers for activity EE are closely coupled with body mass fluctuations and seem to originate in the brain. Several candidate neuromodulators may be involved in the age-related reduction of activity EE that include: orexin, agouti-related proteins and dopaminergic pathways. Unfortunately, the existing body of research has primarily focused on how neuromodulators influence weight gain and only a few studies have been performed in aging models. Recent evidence suggests that activity EE has an important role in dictating lifespan and thus places emphasis on future research to uncover the underlying biological mechanisms. The study of EE continues to unlock clues to aging. IntroductionAmong the enormous literature on theoretical explanations of aging the role of energy expenditure (EE) has received the most attention. For thousands of years, energy expenditure and metabolism have provided an understanding of how we function today, tomorrow, and eventually when we cease to function altogether. The study of EE and aging has been spurred along by the intriguing association between high rates of EE in short-lived mammals and low rates of EE in long-lived mammals. Some propose that EE per lifespan is fixed and abundant usage will accelerate aging (Rubner, 1908). While many works have challenged and severely criticized the rate of living theory (Holloszy and Smith, 1986;Austad and Fischer, 1991), EE and the biological processes that control the machinery are very much under intense study (Speakman, 2005).Energy expenditure has often been purported as a cause of aging without a complete understanding of changes in each of EE components with age. A thorough understanding of the age-related changes in EE components will help reveal the potential compensatory strategies that preserve lifespan. For example, it remains unclear why EE due to physical activity declines across all mammalian phylogenetic lines. Although many hypotheses on aging have involved in some manner the rates of metabolism, the debate on the role of altering EE for enhancing lifespan continues with new data in humans (Manini et al., 2006). The results add new light to the role of EE in preserving average lifespan among older adults.Correspondence: Todd Manini, University of Florida, Institute on Aging, Department of Aging and Geriatric Research, 210 E Mowry Rd, PO Box 112610, Gainesville, FL 32611-2610, tmanini@aging.ufl.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted ...

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“…Mice were tracked for a further 2 weeks on their respective diets. During the 6th week of feeding, voluntary physical activity (individually housed running wheels, which have been shown to correlate well with infrared photoelectric measurements of spontaneous motor activity (Thorburn et al 2000)), resting energy expenditure (REE) and respiratory quotient (RQ; indirect calorimetry; 10 min interval sampling over 75 min during the resting period (daytime)) were measured (Fam et al 2007, Mangiafico et al 2011, Wong et al 2011, Visinoni et al 2012. At the conclusion, mice were anaesthetised in the non-fasted state (0900 h) (Ahren & Scheurink 1998, Fam et al 2007 with an i.p.…”

Section: Feeding Protocol and Energy Balance Measurementsmentioning

confidence: 99%

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

Fam¹,

Sgambellone²,

Ruan³

et al. 2015

Journal of Endocrinology

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Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation. Key Words" diet-induced obesity " high-energy density diet " body weight regulation

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Differential and genetically separable associations of leptin with obesity-related traits

Cited by 17 publications

References 39 publications

Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

Differential Levels of Diabetogenic Stress in Two New Mouse Models of Obesity and Type 2 Diabetes

Energy expenditure and aging

Contribution of the hypothalamus and gut to weight gain susceptibility and resistance in mice

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