Abstract
Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1−/− mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy.
Highlights
Vanins are enzymes that convert pantetheine to pantothenic acid
The levels of vanin activity were evaluated in high fat diet (HFD)-induced obese (DIO) mice as well as Zucker Diabetic Fatty (ZDF)-diabetes rats
In contrast to the results obtained in mice, we found no effect of vanin-inhibition on insulin sensitivity in ZDF-diabetes rats (Fig. 4C)
Summary
Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. We investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. Vanin-1 has recently gained interest as a novel modulator of hepatic glucose- and lipid metabolism, and has been suggested as a potential target to treat metabolic diseases[1,2]. In addition to hepatic lipid metabolism, vanin-1 was recently shown to modulate glucose metabolism by directly enhancing hepatic glucose output[2] These observations point towards vanin-1 inhibition as a potential novel pharmacological target to treat metabolic diseases with enhanced glucose production, such as diabetes. In the current study we set out to study the effect of vanin-1 deficiency on the development of obesity-induced hepatic steatosis and diabetes, as well as the potency of RR6, a novel pantetheinase (vanin) inhibitor, as an anti-diabetic drug using experimental animal models
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