Abstract
Background:We examined the ability of the apolipoprotein AI mimetic peptide L-4F to improve the metabolic state of female and male ob mice and the mechanisms involved.Methods:Female and male lean and obese (ob) mice were administered L-4F or vehicle for 6 weeks. Body weight was measured weekly. Fat distribution, serum cytokines and markers of cardiovascular dysfunction were determined at the end of treatment.Results:L-4F significantly decreased serum interleukin (IL)-6, tumor necrosis factor-α and IL-1β. L-4F improved vascular function, and increased serum adiponectin levels and insulin sensitivity compared with untreated mice. In addition, L-4F treatment increased heme oxygenase (HO)-1, pAKT and pAMPK levels in kidneys of ob animals. pAKT and pAMPK levels were significantly reduced in the presence of an HO inhibitor. Interestingly, L4F did not alter body weight in female mice, but caused a significant reduction in males.Conclusions:L-4F treatments reduced cardiovascular risk factors and improved insulin sensitivity in female ob mice independent of body fat changes. Reduced inflammatory cytokine levels accompanied by increased HO activity, serum adiponectin and improved insulin sensitivity suggest that L-4F may promote the conversion of visceral fat to a healthier phenotype. Therefore, L-4F appears to be a promising therapeutic strategy for treating both cardiovascular risk factors and insulin resistance in obese patients of either gender.
Highlights
Obesity affects over 72 million adults in the United States with a disproportionate prevalence in women.[1,2] Moderate to severe obesity is associated with increased risk for cardiovascular complications and insulin resistance in humans[3,4] and animals.[5]In particular, intra-abdominal fat correlates with insulin resistance and is an important determinant of cardiovascular risk.[6]
Female mice treated with L-4F showed a small but significant increase in the visceral fat to body weight ratio compared with controls (Figure 1c)
The changes we measured in the fat to body weight ratio are consistent with the changes that were measured in body weight, which suggests that L-4F treatment may cause sexually dimorphic responses
Summary
Obesity affects over 72 million adults in the United States with a disproportionate prevalence in women.[1,2] Moderate to severe obesity is associated with increased risk for cardiovascular complications and insulin resistance in humans[3,4] and animals.[5]In particular, intra-abdominal fat correlates with insulin resistance and is an important determinant of cardiovascular risk.[6]. Visceral obesity creates a state of low-grade inflammation characterized by increased pro-inflammatory cytokine levels[7,8,9] that contributes to insulin resistance[10] and oxidative stress that impairs vascular and cardiac function.[5] mice lacking tumor necrosis factor (TNF)-a have significantly improved insulin sensitivity and glucose homeostasis in response to diet-induced obesity.[11,12,13] In addition, ob mice overexpressing adiponectin have reduced inflammation and improved insulin sensitivity, accompanied by an increase in adipocyte number and smaller adipocyte size.[14] These data suggest that promoting the expansion of adipocyte number may prevent or stave off the negative inflammatory effects of larger adipocytes. L-4F improved vascular function, and increased serum adiponectin levels and insulin sensitivity compared with untreated mice. CONCLUSIONS: L-4F treatments reduced cardiovascular risk factors and improved insulin sensitivity in female ob mice independent of body fat changes. Reduced inflammatory cytokine levels accompanied by increased HO activity, serum adiponectin and improved insulin sensitivity suggest that L-4F may promote the conversion of visceral fat to a healthier phenotype. L-4F appears to be a promising therapeutic strategy for treating both cardiovascular risk factors and insulin resistance in obese patients of either gender
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