Molecular mechanisms opposing obesity and skin cancer in response to UCP3 overexpression in epidermis

The ability to increase energy expenditure by burning fats for heat production is a specialized characteristic of mammals that allows for maintenance of core body temperature in cold environments. The molecular mechanisms involved in thermogenesis include the actions of uncoupling proteins which facilitate inefficient conversion of nutrients into cellular energy allowing energy dissipation in the form of heat. Increased energy expenditure resulting from increased uncoupling protein 3 (UCP3) expression in skeletal muscle and adipose tissue can prevent obesity and lower body weight. Here, we demonstrate that UCP3 overexpression in basal epidermis is sufficient to prevent obesity and lower body weight. Furthermore, overexpression of UCP3 in epidermis increases overall glucose tolerance and insulin sensitivity through activation of the energy sensitive kinase, AMP-activated kinase (AMPK) and increased expression of the glucose transporter, Glut1. This provides a proof-of-principle that uncoupled respiration in skin may be a useful target in treating obesity and hyperglycemia. UCP3 overexpression increases lipid oxidation in epidermis that opposes accumulation of biomass needed for keratinocyte proliferation. Studies within provide a link between increased lipid catabolism and inhibition of Akt as a new mechanism of metabolic regulation of cell signaling. UCP3-mediated lipid oxidation leads to altered membrane dynamics and reduced membrane localization of Akt. Inhibition of lipid oxidation rescues Akt activation when UCP3 is overexpressed and activates Akt in normal murine and human keratinocytes. Overexpression of Akt rescues proliferation and carcinogenesis in the presence of UCP3 overexpression in bitransgenic mice. These findings demonstrate that UCP3 overexpression can limit cell proliferation and tumorigenesis in epidermis by a mechanism where mitochondrial metabolism regulates growth signaling.