Triazolo[4,5-d]pyrimidin-5-amines based ERK3 inhibitors fail to demonstrate selective effects on adipocyte function.

Extracellular signal-regulated kinase 3 (ERK3 also designated MAPK6 - mitogen-activated protein kinase 6) is a ubiquitously expressed kinase participating in the regulation of a broad spectrum of physiological and pathological processes. Targeted inhibition of the kinase may allow the development of novel treatment strategies for a variety of types of cancer and somatic pathologies, as well as preserving metabolic health, combat obesity and diabetes. We chose and synthesized three triazolo [4,5-d]pyrimidin-5-amines proposed previously as putative ERK3 inhibitors to assess their selectivity and biological effects in terms of metabolic state impact in living cells. As it was previously shown that ERK3 is a major regulator of lipolysis in adipocytes, we focused on this process. Our new results indicate that in addition to the previously identified lipolytic enzyme ATGL, ERK3 also regulates hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL). Moreover, this kinase also promotes the abundance of fatty acid synthase (FASN) as well as protein kinase cAMP-activated catalytic subunit alpha (PKACα). To investigate various effects of putative ERK3 inhibitors on lipolysis, we utilized different adipocyte models. We demonstrated that molecules exhibit lipolysis-modulating effects; however, the effects of triazolo [4,5-d]pyrimidin-5-amines based inhibitors on lipolysis are not dependent on ERK3. Subsequently, we revealed a wide range of the compounds' possible targets using a machine learning-based prediction. Therefore, the tested compounds inhibit ERK3 in vitro, but the biological effect of this inhibition is significantly overlapped and modified by some other molecular events related to the non-selective binding to other targets.

Platelet-derived lipids promote insulin secretion of pancreatic ß cells.

Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic ß cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from ß cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting ß cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on ß cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.