Overexpression of Growth Differentiation Factor 15 Reduces Blood Pressure and Produces Anti‐neuroinflammatory Effects in Mice with Diet‐induced Obesity

Abstract

The growth differentiation factor 15 (GDF15) is a stress-responsive cytokine, which belongs to the super family of transforming growth factor beta (TGFb). In the past decade, GDF15 has been implicated in multiple biological processes and diseases, including anti-inflammation, anti-obesity and anti-diabetes effects. However, the role of GDF15 in sympathetic regulation of blood pressure has not been reported in the cardiovascular disease state. The purpose of the study was to investigate the effects of GDF15 on the blood pressure and central nervous system neuroinflammatory responses in diet-induced obese mice. NAG-Tg+ transgenic mice (TG) with overexpression of GDF15 and wild-type (WT) littermates were fed on normal chow or high-fat diet (HFD) for 16 weeks. During the experimental period, arterial pressure was recorded by radiotelemetry in conscious mice. WT mice with HFD had higher mean arterial pressure (MAP) compared with the normal diet fed WT mice (WT HFD 110±4 mmHg verse WT 93±4 mmHg). Compared with WT mice with HFD, GDF15 overexpression significantly reduced MAP (TG HFD: 99±3 mmHg verse WT HFD: 110±4 mmHg) accompanied by the decreased urinary norepinephrine excretion and baseline renal sympathetic nerve activity (TG HFD: 38.9±4.1% max verse WT HFD: 61.2±5.6% max). GDF15 TG mice with HFD had lower expressions of pro-inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-a), interleukin 1β (IL-1β), C1q/TNF-related protein-1 (CTRP1) and reduced immune cell infiltration in the hypothalamus and brain stem tissue. A downregulation in GDF15 receptor (GFRAL) expression was detected in brain stem medullary nuclei in WT HFD mice, which was significantly upregulated in GDF15 TG mice with HFD. These data suggest that GDF15 overexpression exerts a potential protective effect on hypertension in obese mice through attenuating sympathetic outflow. The mechanism for this effect involves anti-inflammatory and neuronal protective properties of GDF15 in the central nervous system.