Clock genes as a link between addiction and obesity

In their recent News and Commentary article, Yuferov et al¹ reviewed the evidence for a role of clock genes in modulating drug addiction. They focused on findings in Clock mutant mice.² These mice do not have a functional CLOCK protein (a transcription factor that may regulate the expression of genes with E-box sequences in their promoters) and they express increased reward behaviors in response to cocaine. However, another important phenotype of Clock mutant mice, which may be relevant for drug addiction has not been mentioned. These mice also suffer from obesity and have a serious metabolic syndrome.³ It has already been inferred that obesity and addiction may share common mechanisms. The fact that Clock mutant mice are models for both addiction and obesity may be interpreted as evidence that clock genes participate in brain mechanisms that regulate eating and cocaine addiction (eg, pleasure); for example, through a dopamine neurotransmitter system.² However, an alternative explanation may be that the peripheral action of clock genes, for example on adipose cells, is the common mechanism. Shimba et al⁴ reported that another clock gene product, BMAL1, which acts in concert with CLOCK as a transcription factor, directly regulates lipogenesis. Alterations in the metabolism of fatty acids may significantly modulate the behavioral effects of cocaine.⁵ Since fat metabolism and fatty acids may prominently influence neuronal functioning, it is possible that Clock mutants have an altered cocaine responsiveness, due to both the central and peripheral sites of clock genes action.