Obesity and downregulated hypothalamic leptin receptors in male metallothionein-3-null mice.

In the present study, we examined whether metallothionein-3 (Mt3), a zinc-binding protein that is specifically enriched in a brain, plays a role in obesity and hypothalamic leptin signaling in mice. Upon aging, male Mt3-null mice gained more body weight than male wild-type mice; however, the daily amount of food intake was little different. Rather, the obesity in male Mt3-null mice was likely the result of decreased metabolic rates, as indicated by lower oxygen consumption and carbon dioxide production. Consistent with this, mRNA levels for the mitochondrial proton carrier UCP1 were reduced in brown adipose tissue of Mt3-null mice. Although Mt3-null mice showed increases in serum leptin levels, probably due to increased fat mass, the level of the leptin receptor (Lepr) in the hypothalamus of these mice was significantly reduced. In addition, levels of phosphorylated extracellular signal-regulated kinase (p-Erk-1/2) were also reduced in the hypothalamus of Mt3-null mice. Because zinc released from Mt3 may activate Erk-1/2, we examined whether zinc is involved in the upregulation of Lepr levels through the activation of Erk-1/2. Consistent with this possibility, exposure of hypothalamic cells to zinc activated Erk-1/2 and induced Lepr expression in an Erk-dependent manner. The present results demonstrate that Mt3 in the brain of male mice, particularly in the hypothalamus, may be involved in central leptin signaling and the consequent increase in peripheral energy expenditure. In addition to providing insight into the role of zinc and metallothioneins in the development of obesity, this new information may help design ways to overcome the pervasive problem of obesity.