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Adipose tissue affects metabolic-related diseases because it consists of various cell types involved in fat metabolism and adipokine release. CXC ligand 5 (CXCL5) is a member of the CXC chemokine family and is highly expressed by macrophages in white adipose tissue (WAT). In this study, we generated and investigated the function of CXCL5 in knockout (KO) mice using CRISPR/Cas9. The male KO mice did not show significant phenotype differences in normal conditions. However, proteomic analysis revealed that many proteins involved in fatty acid beta-oxidation and mitochondrial localization were enriched in the inguinal WAT (iWAT) of Cxcl5 KO mice. Cxcl5 KO mice also showed decreased protein and transcript expression of genes associated with thermogenesis, including uncoupling protein 1 (UCP1), a well-known thermogenic gene, and increased expression of genes associated with inflammation. The increase in UCP1 expression in cold conditions was significantly retarded in Cxcl5 KO mice. Finally, we found that CXCL5 treatment increased the expression of transcription factors that mediate Ucp1 expression and Ucp1 itself. Collectively, our data show that Ucp1 expression is induced in adipocytes by CXCL5, which is secreted upon β-adrenergic stimulation by cold stimulation in M1 macrophages. Our data indicate that CXCL5 plays a crucial role in regulating energy metabolism, particularly upon cold exposure. These results strongly suggest that targeting CXCL5 could be a potential therapeutic strategy for people suffering from disorders affecting energy metabolism.

Doxorubicin (DOX) is an antitumor drug, associated with cardiomyopathy. Strategies to address DOX-cardiomyopathy are scarce. Here, we identify the effect of forskolin (FSK) on DOX-induced-asymmetric-dimethylarginine (ADMA) accumulation in monocytoid cells. DOX-challenge led to i) augmented cytotoxicity, reactive-oxygen-species (ROS) production and methyltransferase-enzyme-activity identified as ADMA and s-adenosylhomocysteine (SAH) accumulation (SAH-A). However, except cytotoxicity, other DOX effects were decreased by metformin and FSK. FSK, did not alter the DOX-induced cytotoxic effect, but, decreased SAH-A by >50% and a combination of three drugs restored physiological methyltransferase-enzyme-activity. Together, protective effect of FSK against DOX-induced SAH-A is associated with mitigated methyltransferase-activity, a one-of-a-kind report., Graphical abstract Possible signal pathway by which forskolin regulates arginine methylation. Forskolin prevents doxorubicin-induced methyltransferase activity which mitigates biosynthesis of ADMA and SAH, the intermediate products of protein methylation. ADMA is an endogenous inhibitor of eNOS which catalyses the formation of nitric oxide. Hence, an increase in intracellular or circulating ADMA concentration leads to eNOS uncoupling and endothelial dysfunction. Such an inhibitory effect of FSK has the potential to prevent eNOS uncoupling under DOX insult. (+) – potentiation; Image 2 – inhibition; 1 – Methylation pathway; 2 – Transmethylation pathway; 3 – Remethylation pathway; ADMA – asymmetric dimethylarginine; CVD – cardiovascular disease; DDAH – Dimethylarginine dimethylaminohydrolase; DOX – doxorubicin; ED – endothelial dysfunction; eNOS – endothelial nitric oxide; L-cit – L-citrulline; L-NMMA – L-N-monomethylarginine; MAT – methionine adenosyltransferase; MT – methyltransferases; MS – methionine synthase; Met – S-methionine; NO – nitric oxide; SAM – S-adenosylmethionine; SAH – S-adenosylhomocysteine; SAHH – S-adenosylhomocysteine hydrolase; FSK – Forskolin; HCY – homocysteine; L-arg – L-argininefx1, Highlights • Forskolin has a protective role against doxorubicin-induced pathological side-effects. • Forskolin decreased DXR-induced levels of ADMA and SAH, independent biomarkers in cardiovascular disease. • Forskolin decreased doxorubicin-induced methyltransferase activity. • Forskolin does not interfere with the anticancer effect of doxorubicin.