Obesity and hyperleptinemia in metallothionein (-I and -II) null mice

Abstract

Metallothionein (MT) has several putative roles in metal detoxification, in Zn and Cu homeostasis, in scavenging free radicals, and in the acute phase response. Mice of mixed 129͞Ola and C57BL͞6J background with targeted disruption of MT-I and MT-II genes are more sensitive to toxic metals and oxidative stress. We noted that these animals were larger than most strains of mice, and we systematically studied aspects of their physiology and biochemistry relating to energy metabolism. During the first 2 weeks after weaning, the growth rates of MT-null and C57BL͞6J mice were similar, but the transgenic mice became significantly heavier at age 5-6 weeks. At age 14 weeks, the body weight and food intake of MT-null mice was 16 and 30% higher, respectively, compared with C57BL͞6J mice. Most 22-to 39-week-old male MT-null mice were obese, as shown by increased fat accretion, elevated obese (ob) gene expression, and high plasma leptin levels, similar to those recorded in Zucker fatty ( fa͞fa) rats. Seven-week-old MT-null mice also had significantly higher levels of plasma leptin and elevated expression of ob, lipoprotein lipase, and CCAAT enhancer binding protein ␣ genes as compared with age-matched C57BL͞6J mice. These observations indicate that abnormal accretion of body fat and adipocyte maturation is initiated at 5-7 weeks of age, possibly coincident with sexual maturation. Targeted disruption of MT-I and MT-II genes seems to induce moderate obesity, providing a new obese animal model. A link between MT and the regulation of energy balance is implied.

Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression

“…Mt1 and Mt2 play a role in the oxidative stress response and their deletion in mice resulted in increased drug sensitivity of the liver and development of obesity. 34,35 Differential Mt1 and Mt2 gene expression was also detected at earlier time points (Fig. 2B).…”

Transcriptomal profiling of the cellular response to DNA damage mediated by Slug (Snai2)

“…However, majority of Snai2-target genes (Atm, Bid, p27, Mt1, Cxcl1, Foxg1 and Fos) were downregulated in Snai2-deficient MEFs in response to DNA damage, supporting the view that Snai2 can also behave as a positive transcriptional regulator or act by repressing the transcription of a repressor (Bermejo-Rodriguez et al, 2006). All these novel Snai2 targets have been implicated in DNA damage and survival regulation (Wang et al, 1991;Beattie et al, 1998;Park et al, 2000;Nanda et al, 2001;Katoh and Katoh, 2004;Minn et al, 2005). Thus, the regulation of these genes by Snai2 in response to DNA damage could be important in preserving integrity of tumour target cells and supports the view that failure to control Snai2 expression can produce cancer and alterations in development (Perez-Mancera et al, 2005;Perez-Mancera et al, 2006).…”

Genes regulated by caloric restriction have unique roles within transcriptional networks

“…The CR-upregulated metallothionein genes are most often studied in relation to stress-response, but Mt1 and Mt2 appear to have broad physiological roles even in the absence of stress (Beattie et al, 1998;Waelput et al, 2000;Penkowa, 2006). It has been suggested, for example, that metallothioneins influence energy regulation, since mice lacking Mt1 and Mt2 have higher food intake, elevated plasma leptin concentrations and exhibit obesity following sexual maturation (Beattie et al, 1998).…”

“…It has been suggested, for example, that metallothioneins influence energy regulation, since mice lacking Mt1 and Mt2 have higher food intake, elevated plasma leptin concentrations and exhibit obesity following sexual maturation (Beattie et al, 1998). Additionally, like Col1a1, Col3a1 and Serpinh1, the metallothioneins appear to affect collagen accumulation and development of fibrosis.…”