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Excessive expansion of adipose tissue in obesity typically leads to overflow and accumulation of lipids in other tissues, causing fatty liver disease and atherosclerosis. The intracellular protein, phosphoprotein enriched in astrocytes (PEA)-15 has been linked to metabolic disease but its role in lipid storage has not been examined. To delineate the role of PEA-15 in adipose tissue, we placed PEA-15 mice on a high fat diet. These mice developed increased body weight and greater white adipose tissue expansion compared to high fat diet-fed wild type mice. This was due to increased adipocyte cell size in PEA-15 mice consistent with greater lipid storage capacity. Surprisingly, PEA-15 mice exhibited improvements in whole body insulin sensitivity, lower hepatic weight and decreased serum triglycerides indicating a protective phenotype. To determine effects on atherosclerosis, PEA-15 mice were crossed with the ApoE mice on a high fat diet. Strikingly, these mice were protected from atherosclerosis and had less hepatic lipid accumulation despite increased adiposity. Therefore, we reveal for the first time that PEA-15 plays a novel role in regulating the expansion of adipose tissue. Decreasing PEA-15 expression increases the sequestering of lipids in adipose tissue, protecting other tissues in obesity, thereby improving metabolic health.

Atherosclerotic plaque formation is the result of lipid accumulation in the arterial intima leading to foam cell formation and is exacerbated by high fat diet feeding. The accumulation of lipids in arterial plaques can be viewed as a problem of lipid storage, i.e. adipose depots are not able to efficiently buffer the excessive lipid intake. Insufficient storage capacity can lead to lipid deposition in other metabolic organs, particularly the liver, resulting in a cholesterol imbalance. Fatty liver subsequently results in increased plasma lipids which underlie lipid plaque formation. We have recently demonstrated that a protein previously uncharacterized in the cardiovascular system, phosphoprotein enriched in astrocytes (PEA)−15, plays a central role in maintaining normal arterial function, particularly in response to stress stimuli. PEA-15 acts as a brake on extracellular signal-regulated kinases (ERK) 1/2-dependent gene expression. ERK1/2 are signalling enzymes that control a large variety of cellular processes. Importantly, ERK1/2 activity is also a critical component during adipose tissue expansion. In the current study we hypothesized that PEA-15 can regulate adipose tissue expansion which could ultimately control lipid plaque formation in atherosclerosis.We generated a novel, double knockout (KO) transgenic mouse line null for both PEA-15 and apolipoprotein E (ApoE). Mice were fed a high fat/cholesterol diet (HFD) (42% kcal from fat) for 16 weeks to induce plaque formation. After 16 weeks of HFD, the PEA-15/ApoE KO mice weighed significantly more than ApoE KO mice (PEA-15/ApoE KO - 44.1±1.7 g versus ApoE KO - 38.4±1.3 g, p<0.05, n=6). This was the result of increased white adipose tissue depots in PEA-15/ApoE KO mice. Surprisingly, despite this increased adipose tissue weight, total plaque area in the thoracic aorta was significant decreased in PEA-15/ApoE KO mice (as measured by contrast microscopy 17.8%±2.2% versus 27.6±3.3% in ApoE KO, p<0.05, n=6). In cross sections of these plaques, we found that the caps of the plaques in the PEA-15/ApoE KO mice were thicker. To investigate the lipid storage after the high fat diet, cross sections of the abdominal adipose tissue were examined in these mice. Adipocytes in PEA-15/ApoE KO mice were significant larger (5.7±0.5 μm2 compared to 4.2±0.5 μm2 in ApoE KO, p<0.05, n=7). This suggests that PEA-15 plays a role in the lipid storage capacity of adipocytes. To determine if this is a protective mechanism against lipid deposition in other important peripheral metabolic tissues, such as the liver, we examined hepatic lipid levels. Hepatic triglyceride levels were significantly decreased in PEA-15/ApoE KO mice (72.7±10.2 µg/mg liver versus 114.9±11.1 µg/mg liver in ApoE, p<0.05, n=5–7).Our observations together suggest that PEA-15 plays a role in plaque formation through involvement in lipid deposition. This study demonstrates that PEA-15 protein deletion attenuates atherosclerotic plaque formation. This coincides with an increased lipid storage capacity in adipocytes, thereby protecting other metabolic organs from the associated increased lipid burden. Therefore, decreasing PEA-15 levels and/or activity may be a therapeutic target to alter the progression of atherosclerosis.

Atherosclerotic plaque formation is the result of lipid accumulation in the arterial intima leading to foam cell formation and is exacerbated by high fat diet feeding. The accumulation of lipids in arterial plaques can be viewed as a problem of lipid storage, i.e. adipose depots are not able to efficiently buffer the excessive lipid intake. Insufficient storage capacity can lead to lipid overflow into other organs, particularly the liver, resulting in a cholesterol imbalance. Fatty liver subsequently results in increased plasma lipids which underlie lipid plaque formation. We have recently demonstrated that a protein previously uncharacterized in the cardiovascular system, protein enriched in astrocytes (PEA)−15, plays a central role in maintaining normal arterial function, particularly in response to stress stimuli. Specifically, PEA-15 prevents proliferation by acting as a brake on extracellular signal-regulated kinases (ERK) 1/2-dependent gene expression. ERK1/2 activity is a critical component in adipose tissue expansion. In the current study we hypothesised that PEA-15 can regulate adipose tissue expansion which could ultimately control lipid plaque formation in atherosclerosis. We generated a double knockout (KO) transgenic mouse line null for both PEA-15 and apolipoprotein E (ApoE). Mice were fed a high fat/cholesterol diet (HFD) (42% kcal from fat) for 16 weeks to induce plaque formation. After 16 weeks of HFD, the PEA-15/ApoE KO mice weighed significantly more than ApoE KO mice (PEA-15/ApoE KO – 44.1±1.7 g versus ApoE KO – 38.4±1.3 g, p<0.05, n=6). This was the result of increased white adipose tissue depots in PEA-15/ApoE KO mice. Surprisingly, despite this increased adipose tissue weight, total plaque area in the thoracic aorta was significant decreased in PEA-15/ApoE KO mice (as measured by contrast microscopy 17.8±2.2% versus 27.6±3.3% in ApoE KO, p<0.05, n=6). Abdominal adipose tissue was examined in these mice. While adipocytes were similar in number compared to ApoE KO, adipocytes in PEA-15/ApoE KO mice were significant larger (5.7±0.5 µm2 compared to 4.2±0.5 µm2 in ApoE KO, p<0.05, n=7). This suggests that PEA-15 plays a role in lipid storage capacity in adipocytes. To determine if this is a protective mechanism against lipid absorption in other important peripheral metabolic tissues, such as the liver, we examined hepatic lipid levels. Hepatic triglyceride levels were significantly decreased in PEA-15/ApoE KO mice (72.7±10.2 µg/mg liver versus 114.9±11.1 µg/mg liver in ApoE, p<0.05, n=5–7). In conclusion, this study demonstrates that PEA-15 protein deletion attenuates atherosclerotic plaque formation. This coincides with efficient lipid storage capacity of adipocytes, thereby protecting other metabolic organs from the associated increased lipid burden. Therefore, decreasing PEA-15 levels and/or activity may be a therapeutic target to alter the progression of atherosclerosis.