Elevated Glucocorticoids in Obese-Hyperglycemic Mice

Dubuc, Paul U.; Mobley, Patrick W.; Mahler, Richard J.

doi:10.1055/s-0028-1095645

Cited by 23 publications

(18 citation statements)

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“…Glucocorticoids are potent inhibitors of skin carcinogenesis (35,36) and corticosterone levels are highly elevated in ob/ob mice (37,38). We therefore tested whether the difference in corticosterone levels might explain why ob/ob mice are much less susceptible to skin carcinogenesis than ZIP mice.…”

Section: Resultsmentioning

confidence: 99%

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Ablamunits

Cohen²,

Brazee³

et al. 2006

Cancer Research

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Obesity is typically associated with increased tumor susceptibility, whereas caloric restriction, a regimen resulting in leanness, inhibits carcinogenesis. The link between adiposity and malignancies suggests that adipose tissue may influence carcinogenesis. An adipose tissue hormone, leptin, could be procarcinogenic because it stimulates proliferation in various tissues and tumor cell lines. Leptin may contribute to the correlation between adiposity and malignancies as its levels are usually increased in obese subjects and reduced by caloric restriction. We hypothesized that leptin deficiency, despite obesity, would inhibit carcinogenesis in leptin-null ob/ob mice and tested this hypothesis in two models: (a) two-stage skin carcinogenesis initiated by 7,12-dimethylbenz(a)anthracene and promoted by phorbol 12-myristate 13-acetate (PMA) and (b) p53 deficiency. Contrary to a typical association between obesity and enhanced carcinogenesis, obese ob/ob mice developed induced skin papillomas and spontaneous p53-deficient malignancies, mostly lymphomas, similarly to their lean littermates. Surprisingly, lipodystrophic (ZIP) mice that had very little both adipose tissue and leptin were highly susceptible to carcinogenesis. Hyperphagia, hyperinsulinemia, and hyperglycemia are unlikely to have contributed significantly to the enhancement of carcinogenesis in ZIP mice because similarly hyperphagic, hyperinsulinemic, and hyperglycemic ob/ob mice had normal susceptibility to carcinogenesis. Our data suggest that, in contrast to a well-known correlation between obesity and cancer, the direct effect of adipose tissue may rather be protective. (Cancer Res 2006; 66(17): 8897-902)

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Section: Resultsmentioning

confidence: 99%

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Ablamunits

Cohen²,

Brazee³

et al. 2006

Cancer Research

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“…Perhaps of relevance in this context, circulating glucocorticoids are reported to be elevated in both diabetic rats [29] and obese mice [11,12] before 3 weeks of age, and have been shown to cause decreased synthesis of DNA and the preferential loss of white muscle [15,29]. Further evidence for the involvement of corticosteroids has been provided by work using adrenalectomized mice.…”

Section: Discussionmentioning

confidence: 99%

“…It is conceivable, therefore, that the inherent resistance of muscles from obese mice to the anabolic effects of insulin [9,10] could facilitate a decrease in the post-natal growth of this tissue. Plasma corticosteroid levels are also elevated in ob/ob mice [11,12] and may cause accelerated protein degradation and diversion of amino-acids into excessive gluconeogenesis [13]. If these metabolic abnormalities in obese mice are responsible for their decreased skeletal muscle mass, one would predict that fast and slow phasic muscles would respond differently, since either st~eptozotocin-induced diabetes [14] or corticosteroid injections in rats [15] cause large glycolytic fibres and fast phasic muscles, to lose most weight.…”

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confidence: 99%

A histochemical and morphological study of skeletal muscle from obese hyperglycaemic ob/ob mice

almond

Enser

1984

Diabetologia

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Summary. The histochemical and morphological charactefis= tics of muscles from lean and obese hyperglycaemic ob/ob mice were compared to determine the nature of the low skeletal muscle mass of the latter: Gastrocnemius and biceps brachii muscles from obese ob/ob mice were significantly lighter than those from lean mice; whereas the weights of soleus muscles were not significantly different. The small mass of the biceps brachii muscle resulted from a decrease in diameter of the large glycolytic fast white and fast intermediate fibres and a reduction in the proportion of fast white fibres.The size and frequency of the more oxidative fast red fibres was not different. The histochemical appearance of all fibre types studied from muscles in obese mice was identical to equivalent fibres in lean mice. The fat content of muscles from obese mice was three times greater than in lean mice whereas muscle DNA concentration was similar.Key words: Obese mice, muscle size, fibre type, fibre number, diabetes.Obese hyperglycaemic mice with the ob/ob genome have been used extensively as a model for Type 2 (noninsulin-dependent) diabetes. They are characterized by many abnormalities including hyperphagia, fasting hyperglycaemia, and hyperinsulinaemia. They have fewer insulin receptors and their tissues, particularly muscle, show a marked resistance to the normal metabolic actions of this hormone [1]. Obese mice have similar quantities of total body protein to lean mice [2]. However, extra protein present in their enlarged adipose tissue, liver, and intestine disguises a lower content of skeletal muscle protein [3,4].The smaller amount of muscle could be due to a decrease in the number of muscle fibres, or a reduced volume per fibre, or both. If there were fewer fibres within the muscles of obese mice, it would indicate a difference in pre-natat development compared with lean mice since in mice the majority of muscle fibres are present at or soon after birth [5, 6]-On the other hand, a decrease in the post-natal growth of fibres would be compatible with the other reported metabolic defects in ob/ob mice. Insulin is probably the most important physiological factor regulating the overall protein balance in skeletal muscle [7] since k not only stimulates the uptake of amino-acids and protein synthesis, [8] but also inhibits protein degradation. It is conceivable, therefore, that the inherent resistance of muscles from obese mice to the anabolic effects of insulin [9,10] could facilitate a decrease in the post-natal growth of this tissue. Plasma corticosteroid levels are also elevated in ob/ob mice [11,12] and may cause accelerated protein degradation and diversion of amino-acids into excessive gluconeogenesis [13]. If these metabolic abnormalities in obese mice are responsible for their decreased skeletal muscle mass, one would predict that fast and slow phasic muscles would respond differently, since either st~eptozotocin-induced diabetes [14] or corticosteroid injections in rats [15] cause large glycolytic fibres and fast phasic musc...

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“…Insulin can, under certain circumstances, enhance T cell-mediated cytotoxicity [16]. Plasma cor ticosteroid levels are also raised in obese mice [2,[4][5][6]9] and to a lesser extent in heterozygotes [9]. Primed, sham-operated obese mice yielded only 58°/o of the number of spleen cells obtained from primed lean controls, whilst the figure for adrenalectomised animals was 88°/o.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Obese (ob/ob) Genotype on Spleen Cell Immune Function

Meade¹,

Sheena²,

Mertin³

1979

Int Arch Allergy Immunol

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Spleen cells from mice homozygous for the obese (ob) mutation killed DBA/2 mastocytoma target cells less well than spleen cells from lean littermates or unrelated age- and sex-matched controls of the same strain. Killing was impaired only when the attacker cells were primed in vivo, not following in vitro priming. Hence the effect of the ob/ob genotype is not to produce an irreversible functional change in the lymphocyte, but rather to produce an environment in which lymphocytes are less able to react to priming antigen. Not only were the spleen cells of in vivo primed obese mice less active than those of lean controls, but also their number per spleen was significantly decreased. Such a quantitative difference was no longer found in adrenalectomised animals, but the qualitative difference in spleen cell cytotoxic activity still occurred. This suggests that adrenocortical hyperfunction may affect immune function in obese mice, without necessarily being the only factor in the in vivo environment of obese mouse spleen cells capable of depressing cellular immune reactivity.

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Elevated Glucocorticoids in Obese-Hyperglycemic Mice

Cited by 23 publications

References 0 publications

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

Susceptibility to Induced and Spontaneous Carcinogenesis Is Increased in Fatless A-ZIP/F-1 but not in Obese ob/ob Mice

A histochemical and morphological study of skeletal muscle from obese hyperglycaemic ob/ob mice

Effects of the Obese (ob/ob) Genotype on Spleen Cell Immune Function

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