Abstract 16481: Elevating Hdl Levels in Mice Prevents Age-Induced Decline of Endurance Capacity by Promoting Glycolysis and Lipolysis
Abnormal glucose metabolism is a central feature of disorders associated with increased rates of cardio-vascular disease (CVD). One of the strongest predictors of CVD in the metabolic syndrome is a low level of HDL. Herein we used a genetic mouse model with markedly increased HDL levels (apoAI tg: 174 ± 41 mg/dl) and one with severely reduced HDL levels (apoAI ko: 23 ± 10 mg/dl) compared to wt mice (wt: 70 ± 9 mg/dl) to test the hypothesis that circulating HDL levels may modulate glucose and lipid utilization. Fasting glucose levels were reduced in apoAI tg mice and increased in apoAI ko mice compared to wt mice (respectively 142 ± 5 vs 196 ± 12 vs 160 ± 4 mg/dl; N = 15, P = 0.01). Glucose tolerance was improved in apoAI tg mice and impaired in apoAI ko mice compared to wt mice (AUC 142 ± 5 vs 1041 ± 51 vs 846 ± 56 mg/dl, N = 10, P = 0.02). Fasting lactate levels were increased in apoAI tg mice compared to apoAI ko and wt mice (1.72 ± 0.18 vs 1.4 ± 0.14 vs 1.08 ± 0.09 mmol/L, P = 0.01), suggesting that glycolysis was enhanced in apoAI tg mice compared to wt mice. Body composition analysis revealed that fat mass was reduced in apoAI tg mice and increased in apoAI ko mice compared to wt mice (12 ± 0.7 vs 18 ± 0.8 vs 16 ± 1 % fat of BW, N = 13, P < 0.05) and fasting NEFA levels were increased in apoAI tg mice compared to wt and apoAI ko mice (0.56 ± 0.02 vs 0.44 ± 0.04 vs 0.38 ± 0.02, N = 13, P < 0.05) suggesting that lipolysis in adipose tissue of apoAI tg mice is enhanced compared to wt mice. To understand whether FGF21, a novel inhibitor of lipolysis, may mediate the increased NEFA release observed in apoAI tg mice we determined FGF21 expression in liver. We found that FGF21 expression levels are significantly reduced in apoAI tg mice compared to apoAI ko and wt mice (0.6 ± 0.15 vs 1.4 ± 0.2 vs 2 ± 0.6, N = 5, P = 0.03) suggesting that FGF21 mediated inhibition of lipolysis is reduced in apoAI tg mice. To understand whether this enhancement of glucose and lipid homeostasis prevents age-induced decline in muscle performance, we performed exercise exhaustion tests in aging mice. Endurance capacity was not changed in aging apoAI tg mice compared to apoAI ko and wt mice (-3.3 ± 60 vs -156 ± 65 vs -234 ± 55 meter). Our findings point beyond the traditional scope of HDL-based therapies suggesting novel opportunities for the treatment of metabolic diseases.
- © 2011 by American Heart Association, Inc.