Peptidyl-prolyl Cis/Trans Isomerase NIMA-interacting 1 Associates with Insulin Receptor Substrate-1 and Enhances Insulin Actions and Adipogenesis

Abstract

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that associates with the pSer/Thr-Pro motif and catalyzes cis-trans isomerization. We identifiedIn good agreement with these in vitro data, Pin1 knock-out mice exhibited impaired insulin signaling with glucose intolerance, whereas adenoviral gene transfer of Pin1 into the ob/ob mouse liver mostly normalized insulin signaling and restored glucose tolerance. In addition, it was also demonstrated that Pin1 plays a critical role in adipose differentiation, making Pin1 knock-out mice resistant to diet-induced obesity. Importantly, Pin1 expression was shown to be up-regulated in accordance with nutrient conditions such as food intake or a high-fat diet. Taken together, these observations indicate that Pin1 binds to IRS-1 and thereby markedly enhances insulin action, essential for adipogenesis.

Structure and function of the human parvulins Pin1 and Par14/17

“…Highly increased Pin1 levels induce the onset of obesity, the nonalcoholic fatty liver disease, diabetes mellitus and atherosclerosis (Nakatsu et al, 2011(Nakatsu et al, , 2012Lu et al, 2013;Paneni et al, 2015). Additionally, Pin1 has a biphasic effect on the insulin receptor substrate pathway (Saltiel and Kahn, 2001).…”

“…Under high fat diet (HFD) feeding of mice Pin1 contributes to glucose metabolism, to bone formation and the maintenance of vascular functions like in the development of metabolic syndromes (Nakatsu et al, 2011;Lu et al, 2013;Lee et al, 2014b;Han et al, 2016). Highly increased Pin1 levels induce the onset of obesity, the nonalcoholic fatty liver disease, diabetes mellitus and atherosclerosis (Nakatsu et al, 2011(Nakatsu et al, , 2012Lu et al, 2013;Paneni et al, 2015).…”

The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion

“…Immunoblotting was performed, as previously reported [12,16,17]. Pin1 associates with SIK2 and thereby decreases the expression of p35, a negative regulator of VDCC.…”

“…In addition, interestingly, the Pin1 expressions in metabolic organs were found to be highly upregulated by high-fat diet feeding and under hyperglycemic conditions [12][13][14][15]. Indeed, Pin1 binds to and modulates numerous important proteins that are key to the regulation of glucose and lipid by guest on http://www.jbc.org/ Downloaded from metabolism, including IRS-1, Crtc2 and AMPK [12,16,17].…”

“…Indeed, Pin1 binds to and modulates numerous important proteins that are key to the regulation of glucose and lipid by guest on http://www.jbc.org/ Downloaded from metabolism, including IRS-1, Crtc2 and AMPK [12,16,17]. Thus, Pin1 contributes to the regulation of gluconeogenesis, adipogenesis, fibrosis, fatty acid oxidation and bone differentiation as well as of the onset of metabolic syndromes, such as obesity and nonalcoholic steatohepatitits [12,[16][17][18][19][20].…”