Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain via Alleviation of Hypothalamic Leptin Resistance

Abstract

Leptin resistance is an important mechanism underlying the development and maintenance of obesity and is thus regarded as a promising target of obesity treatment. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissuetype and urokinase-type plasminogen activators, is produced at high levels in adipose tissue, especially in states of obesity, and is considered to primarily be involved in thrombosis. PAI-1 may also have roles in inter-organ tissue communications regulating body weight, because PAI-1 knockout mice reportedly exhibit resistance to high fat diet (HFD)-induced obesity. However, the role of PAI-1 in body weight regulation and the underlying mechanisms have not been fully elucidated. We herein studied how PAI-1 affects systemic energy metabolism. We examined body weight and food intake of PAI-1 knockout mice fed normal chow or HFD. We also examined the effects of pharmacological inhibition of PAI-1 activity by a small molecular weight compound, TM5441, on body weight, leptin sensitivities, and expressions of thermogenesis-related genes in brown adipose tissue (BAT) of HFD-fed wild type (WT) mice. Neither body weight gain nor food intake was reduced in PAI-1 KO mice under chow fed conditions. On the other hand, under HFD feeding conditions, food intake was decreased in PAI-1 KO as compared with WT mice (HFD-WT mice 3.98 ± 0.08 g/day vs HFD-KO mice 3.73 ± 0.07 g/day, P = 0.021), leading to an eventual significant suppression of weight gain (HFD-WT mice 40.3 ± 1.68 g vs HFD-KO mice 34.6 ± 1.84 g, P = 0.039). Additionally, TM5441 treatment of WT mice pre-fed the HFD resulted in a marked suppression of body weight gain in a PAI-1dependent manner (HFD-WT-Control mice 37.6 ± 1.07 g vs HFD-WT-TM5441 mice 33.8 ± 0.97 g, P = 0.017). TM5441 treatment alleviated HFD-induced systemic and hypothalamic leptin resistance, before suppression of weight gain was evident. Moreover, improved leptin sensitivity in response to TM5441 treatment was accompanied by

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

“…Although it is becoming increasing evident that disruption of PAI‐1 protects against obesity in part via enhanced energy expenditure (12,31,32), in the present work, we demonstrated that inhibition of PAI‐1 also enhances adipose tissue lipolysis, thus identifying a critical interrelated mechanism by which targeting PAI‐1 reverses obesity. Treatment with TM5441 resulted in profound induction of phosphorylated PLIN1, a gatekeeper of adipose tissue lipolysis that enhances the activity of ATGL.…”

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

“…Another hallmark of leptin resistance is low-grade inflammation within the hypothalamus [ 81 ]; hence, pharmacological mitigation of these processes could be a new way to restore leptin sensitiveness. Corroborating results showed that hypothalamus inflammation is associated with impaired leptin signalling and plasminogen activator inhibitor-1 (PAI-1) expression [ 123 , 124 ], whose activity was recently extended in metabolism regulation [ 125 , 126 ]. Elevated circulating levels of PAI-1 were found under obesity conditions [ 127 ] and also appeared to have a predictive role for metabolic syndrome [ 127 ].…”

“…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 ].…”

“…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 ]. Obese mice pre-treated with M5441 responded to leptin infusion with sustained suppression of body weight gain as compared with untreated mice, which showed a weak leptin sensitiveness ( Table 1 ) [ 126 ].…”

“…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 ]. Obese mice pre-treated with M5441 responded to leptin infusion with sustained suppression of body weight gain as compared with untreated mice, which showed a weak leptin sensitiveness ( Table 1 ) [ 126 ]. Nowadays, the paucity of human studies considering the anti-obesity effects of PAI-1 antagonism makes clinical application still a distant expectation.…”