Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60-4.51) μM; TCPTP, IC50=4.16(3.49-4.95) μM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63-4.78) μM) and TCPTP (IC50=1.45(1.18-1.78) μM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.
Funktsional'nye narusheniia pri ozhirenii vo mnogom obuslovleny snizheniem chuvstvitel'nosti tkaneĭ k insulinu i leptinu. Odnim iz puteĭ ee vosstanovleniia iavliaetsia ingibirovanie proteinfosfotirozinfosfatazy 1B (PTP1B) i T-kletochnoĭ proteinfosfotirozinfosfatazy (TCPTP) — negativnykh reguliatorov insulinovogo i leptinovogo signalinga. Nesmotria na progress v razrabotke ingibitorov étikh fosfataz kommercheskie preparaty na ikh osnove ne razrabotany, a mekhanizmy deĭstviia malo izucheny. Tsel' raboty sostoiala v issledovanii vliianiia novykh proizvodnykh 4-okso-1,4-digidrotsinnolina (PI04, PI06, PI07) na aktivnost' PTP1B i TCPTP, a takzhe v izuchenii vliianiia ikh piatidnevnogo vnutribriushinnogo vvedeniia (10 mg/kg/sutki) krysam Wistar s indutsirovannym dietoĭ ozhireniem na massu tela i zhira, metabolicheskie i gormonal'nye pokazateli, ékspressiiu genov fosfataz i retseptorov insulina i leptina v pecheni. Pokazano, chto PI04 iavliaetsia miagkim nizkoselektivnym ingibitorom obeikh fosfataz (PTP1B, IC50=3,42(2,60–4,51) mkM; TCPTP, IC50=4,16(3,49–4,95) mkM), v to vremia kak PI06 i PI07 predpochtitel'no ingibiruiut PTP1B (IC50=3,55(2,63–4,78) mkM) i TCPTP (IC50=1,45(1,18–1,78) mkM) sootvetstvenno. PI04 znachimo snizhal potreblenie korma, massu tela i zhira, oslablial giperglikemiiu, normalizoval tolerantnost' k gliukoze, bazovye i stimulirovannye gliukozoĭ urovni insulina i leptina, indeks insulinovoĭ rezistentnosti. Nesmotria na anoreksigennyĭ éffekt, PI06 i PI07 byli menee éffektivnymi, slabo vliiaia na gliukoznyĭ gomeostaz i chuvstvitel'nost' k insulinu. PI04 sushchestvenno povyshal ékspressiiu genov PTP1B i TCPTP i snizhal ékspressiiu genov retseptorov insulina i leptina. PI06 i PI07 slabo vliiali na éti pokazateli. Takim obrazom, PI04 — ingibitor fosfataz PTP1B i TCPTP — s bol'sheĭ éffektivnost'iu v sravnenii s ingibitorami PTP1B (PI06) i TCPTP (PI07) vosstanavlival metabolicheskie i gormonal'nye pokazateli u krys s ozhireniem, chto ukazyvaet na perspektivnost' sozdaniia smeshannykh PTP1B/TCPTP-ingibitorov dlia korrektsii metabolicheskikh rasstroĭstv.
Keywords: T-cell protein phosphotyrosine phosphatase; appetite; inhibitor; insulin; leptin; liver; obesity; protein phosphotyrosine phosphatase 1B.