Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice.

Harini Sampath, Ayesha K. Batra, Vladimir Vartanian, J. Russ Carmical, Deborah Prusak, Irena B. King, Brian Lowell, Lauriel F. Earley, Thomas G. Wood, Daniel Marks, Amanda McCullough, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1(-/-) mice. Following a 5-wk high-fat diet challenge, neil1(-/-) mice gained significantly more body weight than neil1(+/+) littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1(-/-) mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1(-/-) mice following high-fat diet challenge compared with chow-fed or neil1(+/+) counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein content in neil1(-/-) mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications potentially by lowering the threshold for tolerance of cellular oxidative stress in neil1(-/-) mice.

Original languageEnglish (US)
JournalAmerican journal of physiology. Endocrinology and metabolism
Volume300
Issue number4
DOIs
StatePublished - Apr 2011

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Penetrance
Adiposity
High Fat Diet
Phenotype
Oxidative Stress
Obesity
Mitochondrial DNA
Oxygen Consumption
Liver
DNA Glycosylases
Indirect Calorimetry
Glucose Intolerance
Mitochondrial Proteins
Hyperinsulinism
DNA Repair
DNA Damage
Adipose Tissue
Heart Diseases
Body Weight
Lipids

ASJC Scopus subject areas

  • Medicine(all)

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Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice. / Sampath, Harini; Batra, Ayesha K.; Vartanian, Vladimir; Carmical, J. Russ; Prusak, Deborah; King, Irena B.; Lowell, Brian; Earley, Lauriel F.; Wood, Thomas G.; Marks, Daniel; McCullough, Amanda; Lloyd, Robert (Stephen).

In: American journal of physiology. Endocrinology and metabolism, Vol. 300, No. 4, 04.2011.

Research output: Contribution to journalArticle

Sampath, Harini ; Batra, Ayesha K. ; Vartanian, Vladimir ; Carmical, J. Russ ; Prusak, Deborah ; King, Irena B. ; Lowell, Brian ; Earley, Lauriel F. ; Wood, Thomas G. ; Marks, Daniel ; McCullough, Amanda ; Lloyd, Robert (Stephen). / Variable penetrance of metabolic phenotypes and development of high-fat diet-induced adiposity in NEIL1-deficient mice. In: American journal of physiology. Endocrinology and metabolism. 2011 ; Vol. 300, No. 4.
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AU - Carmical, J. Russ

AU - Prusak, Deborah

AU - King, Irena B.

AU - Lowell, Brian

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AB - Exposure to chronic and acute oxidative stress is correlated with many human diseases, including, but not limited to, cancer, heart disease, diabetes, and obesity. In addition to cellular lipids and proteins, cellular oxidative stress can result in damage to DNA bases, especially in mitochondrial DNA. We previously described the development of spontaneous late-onset obesity, hepatic steatosis, hyperinsulinemia, and hyperleptinemia in mice that are deficient in the DNA glycosylase nei-like 1 (NEIL1), which initiates base excision repair of several oxidatively damaged bases. In the current study, we report that exposure to a chronic oxidative stress in the form of a high-fat diet greatly accelerates the development of obesity in neil1(-/-) mice. Following a 5-wk high-fat diet challenge, neil1(-/-) mice gained significantly more body weight than neil1(+/+) littermates and had increased body fat accumulation and moderate to severe hepatic steatosis. Analysis of oxygen consumption by indirect calorimetry indicated a modest reduction in total oxygen consumption in neil1(-/-) mice that was abolished upon correction for lean body mass. Additionally, hepatic expression of several inflammatory genes was significantly upregulated in neil1(-/-) mice following high-fat diet challenge compared with chow-fed or neil1(+/+) counterparts. A long-term high-fat diet also induced glucose intolerance as well as a significant reduction in mitochondrial DNA and protein content in neil1(-/-) mice. Collectively, these data indicate that NEIL1 deficiency results in an increased susceptibility to obesity and related complications potentially by lowering the threshold for tolerance of cellular oxidative stress in neil1(-/-) mice.

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