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Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins.

ABSTRACT: The IfitmDel mouse lacks all five of the Ifitm genes via LoxP deletion. This animal breeds normally with no obvious defect in development. The IfitmDel animals exhibit a steady and significantly enhanced weight gain relative to wild-type controls beginning about three months of age and under normal feeding conditions. The increased weight corresponds with elevated fat mass, and in tolerance tests they are hyporesponsive to insulin but respond normally to glucose. Both young (4 mo) and older (12 mo) IfitmDel mice have enhanced levels of serum leptin suggesting a defect in leptin/leptin receptor signaling. Analysis of the gene expression profiles in the hypothalamus of IfitmDel animals, compared to WT, demonstrated an altered ratio of Pomc and Npy neuropeptide expression, which likely impairs the satiation response of the IfitmDel animal leading to an increased eating behavior. Also elevated in hypothalamus of IfitmDel mice were pro-inflammatory cytokine expression and reduced IL-10. Anatomical analysis of the hypothalamus using immunohistochemistry revealed that microglia exhibit an abnormal morphology in IfitmDel animals and respond abnormally to Poly:IC challenge. These abnormalities extend the phenotype of the IfitmDel mouse beyond abnormal responses to viral challenge to include a metabolic phenotype and weight gain. Further, this novel phenotype for the IfitmDel mouse could be related to abnormal neuropeptide production, inflammatory status and microglia status in the hypothalamus.

SUBMITTER: Wee YS

PROVIDER: S-EPMC4391874 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins.

Wee Yin Shen YS Weis Janis J JJ Gahring Lorise C LC Rogers Scott W SW Weis John H JH

PloS one 20150409 4

The IfitmDel mouse lacks all five of the Ifitm genes via LoxP deletion. This animal breeds normally with no obvious defect in development. The IfitmDel animals exhibit a steady and significantly enhanced weight gain relative to wild-type controls beginning about three months of age and under normal feeding conditions. The increased weight corresponds with elevated fat mass, and in tolerance tests they are hyporesponsive to insulin but respond normally to glucose. Both young (4 mo) and older (12 ...[more]

PMID: 25856311

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Project description:Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of subjects with adult-onset asthma. However, whether age of asthma onset modifies the association between obesity and asthma is unknown.We sought to compare the associations between body mass index (BMI) categories with physiological, inflammatory, and clinical parameters across age of asthma onset phenotypes; and to compare the rate of BMI change in relation to asthma duration, by age of onset asthma phenotypes.From the Severe Asthma Research Program, we defined age of asthma onset as early (<12 years of age) and late (?12 years of age). Comparisons of BMI categories were done within age-of-onset groups, and obesity was also compared across these groups. Multivariable logistic regression analysis was done to evaluate the association between BMI categories with health care use and respiratory symptoms and multivariable linear regression for the association between duration of asthma and weight gain (BMI change per year). An interaction between obesity and age of asthma onset was included in the multivariable analyses.The study population consisted of 1049 subjects, and the median age for asthma onset was 10 years (interquartile range, 4-25 years); 48% had late-onset asthma (?12 years of age), and 52% had early-onset asthma (<12 years of age). Compared with obese subjects with late-onset asthma, obese subjects with early-onset asthma had more airway obstruction, bronchial hyperresponsiveness, and higher odds ratios of ever having 3 or more previous oral steroid tapers per year or intensive care unit admissions for asthma per preceding year (interactions between obesity and age of asthma onset were P = .055 and P = .02, respectively). In subjects with early-onset asthma but not in subjects with late-onset asthma, there was a significant association between increasing BMI and duration of asthma after adjusting for confounders. The interaction between asthma duration and age of asthma onset was a P value of less than .01.Asthmatic subjects are differentially affected by obesity based on whether they had asthma early (<12 years of age) or later in life. These results highlight the need to understand obesity as a comorbidity that affects specific clinical phenotypes and not all asthma subjects alike.

Dataset Information

Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins.

Publications

Age-related onset of obesity corresponds with metabolic dysregulation and altered microglia morphology in mice deficient for Ifitm proteins.

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