Hypothalamic CDK4 Regulates Thermogenesis by Modulating the Sympathetic Innervation and Activation of Brown Adipose Tissue

Cell cycle regulators, such CDK4, have previously been shown to be involved in the regulation of oxidative processes. Oxidative metabolism is indeed required for the thermogenic function of BAT. This study investigated the role of CDK4 in BAT function. To this end, we examined metabolic parameters, thermogenesis, and interscapular BAT (iBAT) morphology in a global Cdk4 knockout (Cdk4-/-) mouse, and BAT- and VMH-specific Cdk4 knockout mice. iBAT from Cdk4-/- mice exhibited fewer lipid droplets, increased mitochondrial volume, and increased expression of canonical thermogenic genes, rendering these animals more thermogenic and resistant to cold exposure. These effects were not cell-autonomous, since the BAT-specific deletion (Ucp1-Cre driven) of Cdk4 did not affect thermogenesis in mice. Brown adipose tissue (BAT) maintains body temperature during cold challenges through non-shivering thermogenesis. This process is tightly regulated by several hypothalamic areas, including the ventromedial hypothalamus (VMH), that modulate BAT activation via the sympathetic nervous system. Indeed, the sympathetic innervation of iBAT was also increased in Cdk4-/- mice, suggesting that CDK4 expressed in the central nervous system may mediate the increased thermogenic capacity of these animals. We thus examined the effects of VMH neuron-specific Cdk4 deletion, and found that these mice display increased iBAT sympathetic innervation and enhanced cold tolerance, similar to Cdk4-/- mice. Overall, these data provide new evidence showing that CDK4 in the VMH modulates thermogenesis by regulating the sympathetic innervation of iBAT. We show for the first time that CDK4, not only negatively regulates directly the oxidative pathways, such as observed in muscle cells, but also have a central control in the control of the metabolism of the whole organism through its action in the brain. This raises a new paradigm in our knowledge of the function of CDK4.