School of Medicine and Health Sciences Poster Presentations
Sympathetic Overactivity Contributes to the Pathogenesis of Non-alcoholic Fatty Liver Disease During Diet-induced Obesity
Poster Number
280
Document Type
Poster
Publication Date
3-2016
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with the development of obesity and is a significant contributor to chronic liver, metabolic, and cardiovascular diseases. We have recently shown that hepatic sympathetic nerve activity is significantly elevated in mice fed a high fat diet (HFD; 33±2 vs. 63±5 spikes/s, normal chow vs. HFD; p<0.05), although the contribution of the sympathetic nervous system to NAFLD pathology remains unclear. Therefore, we tested the hypothesis that sympathetic overactivity contributes to NAFLD during diet-induced obesity. Male C57B1/6 mice were fed a HFD (60% fat) or normal chow (5% fat) for 15 weeks. 6-hydroxydopamine (6-OHDA, 150 mg/kg i.p.) was then administered to selectively destroy sympathetic nerves, or vehicle control (n=4/group), and mice were sacrificed 3 days later. 6-OHDA treatment did not influence body weight (e.g. 41±3 vs. 40±2 g; HFD-vehicle vs. HFD-OHDA; p>0.05) or visceral adipose tissue mass in normal chow or HFD fed animals. However, HFD resulted in significant increases in liver weight (1.0±0.1 vs. 1.8±0.1 g normal chow-vehicle vs. HFD-OHDA; p<0.05) and selective ablation of sympathetic nerves rescued HFD-induced hepatomegaly (1.3±0.2 g; p>0.05 vs. normal chow). In line with this, histological examination (H&E staining) revealed widespread hepatic lipid accumulation in HFD fed mice, which was reduced to normal levels following 6-OHDA administration (figure). Diet-induced obesity also resulted in elevations in plasma glucose (172±13 vs. 249±20 mg/dl; normal chow-vehicle vs. HFD-vehicle; p<0.05), and ablation of sympathetic nerves restored HFD-mediated hyperglycemia (160±7 mg/dl; HFD-OHDA; p>0.05 vs. normal chow). Concomitant with this, 6-OHDA administration in HFD fed animals was associated with a reduction in hepatic mRNA markers of gluconeogenesis (e.g. G6PC 6.6±1.0 vs. 3.2±0.7 fold normal chow-vehicle; HFD-vehicle vs. HFD-OHDA; p<0.05) and lipogenesis (e.g. Srebp-1c 2.0±0.3 vs. 0.8±0.3 fold normal chow-vehicle; HFD-vehicle vs. HFD-OHDA; p<0.05). Collectively, these findings demonstrate that removal of sympathetic nerve activity rescues obesity-induced hepatomegaly, hepatic steatosis and hyperglycemia, independent of an effect on body weight and adiposity. Moreover, this data reveals a novel role for the sympathetic nervous system in HFD-mediated NAFLD and suggest that targeting hepatic sympathetic overactivity may represent a novel therapeutic approach to treat NAFLD.
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Open Access
1
Sympathetic Overactivity Contributes to the Pathogenesis of Non-alcoholic Fatty Liver Disease During Diet-induced Obesity
Non-alcoholic fatty liver disease (NAFLD) is associated with the development of obesity and is a significant contributor to chronic liver, metabolic, and cardiovascular diseases. We have recently shown that hepatic sympathetic nerve activity is significantly elevated in mice fed a high fat diet (HFD; 33±2 vs. 63±5 spikes/s, normal chow vs. HFD; p<0.05), although the contribution of the sympathetic nervous system to NAFLD pathology remains unclear. Therefore, we tested the hypothesis that sympathetic overactivity contributes to NAFLD during diet-induced obesity. Male C57B1/6 mice were fed a HFD (60% fat) or normal chow (5% fat) for 15 weeks. 6-hydroxydopamine (6-OHDA, 150 mg/kg i.p.) was then administered to selectively destroy sympathetic nerves, or vehicle control (n=4/group), and mice were sacrificed 3 days later. 6-OHDA treatment did not influence body weight (e.g. 41±3 vs. 40±2 g; HFD-vehicle vs. HFD-OHDA; p>0.05) or visceral adipose tissue mass in normal chow or HFD fed animals. However, HFD resulted in significant increases in liver weight (1.0±0.1 vs. 1.8±0.1 g normal chow-vehicle vs. HFD-OHDA; p<0.05) and selective ablation of sympathetic nerves rescued HFD-induced hepatomegaly (1.3±0.2 g; p>0.05 vs. normal chow). In line with this, histological examination (H&E staining) revealed widespread hepatic lipid accumulation in HFD fed mice, which was reduced to normal levels following 6-OHDA administration (figure). Diet-induced obesity also resulted in elevations in plasma glucose (172±13 vs. 249±20 mg/dl; normal chow-vehicle vs. HFD-vehicle; p<0.05), and ablation of sympathetic nerves restored HFD-mediated hyperglycemia (160±7 mg/dl; HFD-OHDA; p>0.05 vs. normal chow). Concomitant with this, 6-OHDA administration in HFD fed animals was associated with a reduction in hepatic mRNA markers of gluconeogenesis (e.g. G6PC 6.6±1.0 vs. 3.2±0.7 fold normal chow-vehicle; HFD-vehicle vs. HFD-OHDA; p<0.05) and lipogenesis (e.g. Srebp-1c 2.0±0.3 vs. 0.8±0.3 fold normal chow-vehicle; HFD-vehicle vs. HFD-OHDA; p<0.05). Collectively, these findings demonstrate that removal of sympathetic nerve activity rescues obesity-induced hepatomegaly, hepatic steatosis and hyperglycemia, independent of an effect on body weight and adiposity. Moreover, this data reveals a novel role for the sympathetic nervous system in HFD-mediated NAFLD and suggest that targeting hepatic sympathetic overactivity may represent a novel therapeutic approach to treat NAFLD.
Comments
Presented at: GW Research Days 2016