Inhibition of PAI‐1 Promotes Lipolysis and Enhances Weight Loss in Obese Mice

Abstract

Objective: This study investigates the therapeutic potential of a small molecule inhibitor of plasminogen activator inhibitor-1 (PAI-1), TM5441, in reversing diet-induced obesity in mice. Methods: Wild-type C57BL/6J mice were fed a high-fat high-sugar (HFHS) diet for 8 weeks to induce obesity. After the first 8 weeks, TM5441 was added to the diet for an additional 8 weeks. In order to determine the efficacy of PAI-1 inhibition in conjunction with dietary modification, mice were fed an HFHS diet for 8 weeks to induce obesity and were then switched to a low-fat diet with or without TM5441 for an additional 2 to 8 weeks. Results: Obese mice showed weight reduction and significant improvement in hepatic steatosis when TM5441 was added to the HFHS diet. Obese mice that were treated with TM5441 in conjunction with dietary modification showed enhanced weight loss and a more rapid reversal of hepatic steatosis compared with obese mice treated with dietary modification alone. The enhanced weight loss among mice treated with TM5441 was associated with increased adipose tissue expression of adipose triglyceride lipase, phosphorylated hormone-sensitive lipase, and phosphorylated perilipin-1 as well as induction of adipose tissue lipolysis. Conclusions: Pharmacologic PAI-1 inhibition stimulates adipose tissue lipolysis and enhances weight loss in obese mice.

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation

“…PAI-1 expression is dramatically up-regulated in AT in humans with obesity and mice with HFD-induced obesity (111,112). PAI-1 deficiency and PAI-1 inhibitor treatment can protect against HFD-induced obesity, insulin resistance, and liver steatosis (113)(114)(115), partially via the enhanced energy expenditure associated with alleviated hypothalamic leptin resistance (116) and increased adipocyte lipolysis (114,117). The pro-inflammatory cytokines TNF-a and IL-6 stimulate PAI-1 expression in human AT and adipocytes via NF-kB activation, suggesting a close relationship between PAI-1 and obesity-induced inflammation (118,119).…”

Efficacy of Probiotic Strains Lactobacillus sakei Probio65 and Lactobacillus plantarum Probio-093 in Management of Obesity: An In Vitro and In Vivo Analysis

“…PAI-1 itself is a glycoprotein and is known to inhibit plasminogen activation in blood and is also upregulated in obesity with an increased risk of glucose intolerance, hypertension, hyperinsulinemia, insulin hindrance, NIDDM (non-insulin-dependent diabetes mellitus), and accelerated atherosclerosis [ 48 , 49 , 50 ]. In addition, clinical trials of obese humans showed significant weight loss with surgical treatment with a control diet, and, consequently, PAI-1 expression was also reduced [ 49 , 50 , 51 , 52 , 53 , 54 ]. Findings suggest that some hormones or cytokines are involved in the elevated expression of PAI-1, including TNF-α, TGF-β, proinsulin, and triglycerides.…”

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

“…Hence, in vivo disruption of PAI-1 protects against obesity in part via enhanced EE [ 129 ]. Indeed, increased body weight due to energy overload was suppressed following the inhibition of PAI-1 by M5441 in association with an upregulation of thermogenic genes (i.e., UCP-1 , DIO-2 , CIDEA , PRDM-16 ) in brown depots [ 126 ] and amelioration of lipid turnover [ 130 ]. In this scenario, decreased plasma leptin levels were observed, suggesting that the metabolic benefits associated with PAI-1 inhibition could be due to the recovery of leptin sensitivity [ 126 ].…”