Year: 2018
Type: dissertation
Abstract: Insulin resistance is a characteristic finding in hyperglycemia and type 2 diabetes.Sirtuin 1 (SIRT1) is a NAD + -dependent deacetylase involved in the regulation of insulin sensitivity, mitochondrial function, energy metabolism and adipocyte metabolism.Skeletal muscle and adipose tissue are the important insulin-sensitive tissues responsible for maintaining whole body glucose homeostasis.We investigated the association of SIRT1 expression with energy expenditure and insulin sensitivity in these tissues in humans.We showed that energy expenditure associates with insulin sensitivity during the hyperinsulinemic euglycemic clamp, and SIRT1 mRNA expression significantly correlated with the expression of genes regulating energy metabolism and mitochondrial function.We demonstrated that SIRT1 expression in muscle and adipose tissue is associated with energy expenditure and insulin sensitivity.SIRT1 regulates energy metabolism by interacting with AMPK, a master cellular energy sensor, and PGC-1α, a central regulator of mitochondrial biogenesis.SIRT1 activation has been a proven strategy of extending the life span in animal models by delaying the development of age-related diseases and preventing metabolic syndrome.SIRT1 activators, including plant polyphenols such as resveratrol, have beneficial effects on glucose homeostasis, insulin sensitivity and energy metabolism.We aimed to elucidate the potential effects of the novel plant-derived compounds strigolactone analogue GR24 and pinosylvin on SIRT1 function, glucose uptake, mitochondrial biogenesis and gene expression in skeletal muscle cells.We demonstrated in L6 skeletal muscle myotubes with resveratrol as a reference compound that strigolactone GR24 upregulated and activated SIRT1 without activating AMPK, enhanced the production of NAD + , which is an essential SIRT1 substrate, and increased glucose uptake, insulin signaling, GLUT4 translocation and mitochondrial biogenesis.Pinosylvin activated SIRT1 in vitro and stimulated glucose uptake through the activation of AMPK.Obesity is characterized by excess fat accumulation in white adipose tissue, which triggers chronic low-grade inflammation through secretion of pro-inflammatory factors by the enlarged adipocytes and infiltrated macrophages.This affects glucose and lipid metabolism in adipose tissue, inducing type 2 diabetes.SIRT1 activation inhibits adipogenesis by regulating the key adipogenic transcription factors, PPARγ and C/EBPα.We aimed to investigate the role of strigolactone GR24 and pinosylvin in adipogenesis and inflammation of 3T3-L1 adipocytes with resveratrol as a reference compound.GR24 upregulated SIRT1, enhanced NAD + production and inhibited the activation of NF-κB.GR24 and pinosylvin attenuated adipogenesis via downregulating PPARγ and C/EBPα and protected against inflammation by inhibiting TNF-αstimulated IL-6 secretion.In conclusion, our studies demonstrated promising novel therapies via SIRT1 activation in the treatment of insulin resistance and obesity-associated diseases.
Author: Shalem Modi
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Itä-Suomen Yliopisto
OpenAlex ID: W3208404549