eNOS phosphorylation on serine 1176 affects insulin sensitivity and adiposity

Abstract

Phosphorylation of endothelial nitric oxide synthase (eNOS) is an important regulator of its enzymatic activity. We generated knockin mice expressing phosphomimetic (SD) and unphosphorylatable (SA) eNOS mutations at S1176 to study the role of eNOS phosphorylation. The single amino acid SA mutation is associated with hypertension and decreased vascular reactivity, while the SD mutation results in increased basal and stimulated endothelial NO production. In addition to these vascular effects, modulation of the S1176 phosphorylation site resulted in unanticipated effects on metabolism. The eNOS SA mutation results in insulin resistance, hyperinsulinemia, adiposity, and increased weight gain on high fat. In contrast, the eNOS SD mutation is associated with decreased insulin levels and resistance to high fat-induced weight gain. These results demonstrate the importance of eNOS in regulation of insulin sensitivity, energy metabolism, and bodyweight regulation, and suggest eNOS phosphorylation as a novel target for the treatment of obesity and insulin resistance.

The anti-obesogenic effects of nitric oxide.

“…Furthermore, our studies show that mice overexpressing eNOS acquire an antiobesogenic phenotype characterized by resistance to accumulation of white adipose tissue in response to a high fat diet, a higher metabolic rate, resistance to diet-induced hyperinsulinemia, and remarkably lower plasma levels of FFAs and TGs (Chapter III) 286 . Our findings were supported by results from an investigation of an eNOS phosphomimetic point mutant mouse model that was published shortly after our study 543,544 . Mutation of serine 1176 of eNOS to an aspartic acid resulted in increased endothelial NO production as well as resistance to diet-induced weight gain and hyperinsulinemia; mutation of the residue to an alanine, which cannot be phosphorylated, resulted in insulin resistance and features of metabolic syndrome 195,544 .…”

“…Our findings were supported by results from an investigation of an eNOS phosphomimetic point mutant mouse model that was published shortly after our study 543,544 . Mutation of serine 1176 of eNOS to an aspartic acid resulted in increased endothelial NO production as well as resistance to diet-induced weight gain and hyperinsulinemia; mutation of the residue to an alanine, which cannot be phosphorylated, resulted in insulin resistance and features of metabolic syndrome 195,544 .…”

“…Additionally, there may be implications for eNOS-mediated HISS release, which enhances the vasodilatory properties of insulin. That eNOS prevents hyperinsulinemia in two separate genetic gain-offunction studies 160,544 suggests further that it could impact glucose metabolism directly by modulating insulin release. Other isoforms of NOS appear to promote deleterious changes in metabolism.…”

Reciprocal Relationship Between Insulin Resistance and Disturbed Adma/No Axis in Gestational Diabetes Mellitus.

“…Such relationship between NO level and IR could be attributed the fact that insulin metabolic signaling increases endothelial cell NO production, so impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation through reduction of NO production by endothelium (44,45) . Moreover, IR induces pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling leading to imbalance between NO production and secretion of endothelin-1 and induces endothelial dysfunction (46) which is characterized by reduced production of NO, thus creating a vicious circle (47) .…”

Персонифицированное Применение Метформина С Позиции Фармакогенетики (Обзор)

“…Ïîëèìîð-ôèçì G894T èìååò ðàçëè÷íîå çíà÷åíèå â çàâèñèìîñòè îò ýòíè÷åñêîé ïðèíàäëåaeíîñòè ïàöèåíòà (àçèàòû è åâðî-ïåéöû) è èìååò íåîäíîçíà÷íûé õàðàêòåð, â òî âðåìÿ êàê íåò ôóíêöèîíàëüíûõ ðàçëè÷èé ÎÍÏ Ñ786Ò äëÿ ðàçíûõ ýòíè÷åñêèõ ãðóïï. Òåì íå ìåíåå â íåêîòîðûõ èññëåäîâà-íèÿõ áûëà âûÿâëåíà ñòðîãàÿ àññîöèàöèÿ ãåíîòèïà ãîìî-çèãîòû ïî àëëåëè Ò ñ èíñóëèíîðåçèñòåíòíîñòüþ ó ïàöè-åíòîâ ñ ÑÄ2 òèïà è êàðäèîìèïàòèÿìè ñðåäè åâðîïåéöåâ [51] è ÿïîíöåâ [29], è ñ ïîâûøåííûì óðîâíåì ãëþêîçû â êðîâè ó aeèòåëåé Ñàóäîâñêîé Àðàâèè [7]. Ýêñïåðèìåíòû, ïðîâåä¸ííûå íà ãðûçóíàõ, ïîêàçàëè, ÷òî ïîëó÷åííàÿ âñëåäñòâèå 3 ìåñ âûñîêîêàëîðèéíîé äèå-òû èíñóëèíîðåçèñòåíòíîñòü ó aeèâîòíûõ íàðóøàåò ôîñ-ôîðèëèðîâàíèå -àêòèâàöèþ -eNOS.…”