Pleiotrophin deletion alters glucose homeostasis, energy metabolism and brown fat thermogenic function in mice

Abstract

Abstract Aims/hypothesis Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this cytokine can play a regulatory role in glucose and lipid homeostasis. Methods To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted Ptn-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24ºC and 30ºC. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 µg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR). Results Ptn deletion was associated with a reduction in total body fat (20.2% in Ptn +t+ vs 13.9% in Ptn -I- mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in Ptn+t+ vs 273% in Ptn _1_ mice). We found that Ptn -t- mice exhibited a significantly lower QUICK.l value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in Ptn+t+ mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in Ptn -I- than Ptn +!+ mice ( 42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T 3 and mitochondrial uncoupling protein-1 in the brown adipose tissue of Ptn _,_ mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression ofthe brown adipocyte markers Cidea (20% reduction), Prdml 6 (21 % reduction), and Pgcl-a (also known as Ppargcl a, 11 % reduction). Conclusions/interpretation Our results revea] for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynarnics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatrnent of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.