Pyruvate carboxylase supports basal ATP-linked respiration in human pluripotent stem cell-derived brown adipocytes

        Brown adipose tissue or BAT is the adipocytes that have a specific physiology in maintaining body temperature via thermogenesis. BAT activity is mainly regulated by the sympathetic nervous system, which stimulates the thermogenic response while simultaneously increasing the uptake of the oxidative substrates such as glucose and triglycerides needed to respond to cold. When active, BAT is able to uptake and dispose of large quantities of lipid and glucose from the circulation, a trait that has enabled its detection in humans and would be of substantial benefit to obese patients suffering from insulin resistance and hyperlipidemia. In collaboration with Professor Stephen Dalton at the University of Georgia, USA, Professor Sarawut Jitrapakdee’s research team has found that the pyruvate carboxylase (PC), a lipogenic enzyme is overexpressed during brown adipocytes differentiation, suggesting its crucial role between fuel oxidation and thermogenesis.  His research team used CRISPR Cas9 genome editing technology to knock out PC gene in human embryonic stem cells. They found that although ablation of PC gene did not impair brown adipocyte differentiation, PC KO brown adipocytes showed the impairment of ATP-link respiration under basal and thermogenic-induced conditions. Furthermore, PC KO brown adipocytes showed increased spare mitochondrial respiratory capacity, suggesting a compensatory mechanism to protect PC KO cells from ATP-depletion.

References
Lao-On U, Cliff TS, Dalton S, Jitrapakdee S. Pyruvate carboxylase supports basal ATP-linked respiration in human pluripotent stem cell-derived brown adipocytes. Biochem Biophys Res Commun. 2021 Sep 10;569:139-146.

DOI: 10.1016/j.bbrc.2021.06.096