Functional Adiponectin Resistance at the Level of the Skeletal Muscle in Mild to Moderate Chronic Heart Failure

Abstract

Background-Adiponectin is an antiinflammatory, insulin-sensitizing, and antiatherogenic adipocytokine that plays a fundamental role in energy homeostasis. In patients with chronic heart failure (CHF), high circulating adiponectin levels are associated with inverse outcome. Recently, adiponectin expression has been identified in human skeletal muscle fibers. We investigated the expression of adiponectin, the adiponectin receptors, and genes involved in the downstream lipid and glucose metabolism in the skeletal muscle of patients with CHF. Methods and Results-Muscle biopsies (vastus lateralis muscle) were obtained from 13 patients with CHF and 10 healthy subjects. mRNA transcript levels of adiponectin, adiponectin receptors (AdipoR1 and AdipoR2), and downstream adiponectin-related enzymes were quantified by real-time reverse transcriptase polymerase chain reaction. Adiponectin expression in the skeletal muscle of patients with CHF was 5-fold higher than in healthy subjects (PϽ0.001), whereas AdipoR1 was downregulated (Pϭ0.005). In addition, the expression of the main genes involved in downstream pathway (peroxisome proliferator-activated receptor-␣ [PPAR-␣] and both AMP-activated protein kinase-␣1 and -␣2 subunits) as well as their target genes in lipid (acyl-coenzyme A dehydrogenase C-14 to C-12 straight chain) and glucose metabolism (hexokinase-2) were significantly reduced in CHF. The strong positive correlation found between AdipoR1 and PPAR-␣/AMP-activated protein kinase gene expression was confirmed in PPAR-␣ null mice, suggesting a cause-and-effect relationship. Immunohistochemical staining confirmed the presence of adiponectin in the skeletal muscle. Conclusions-Despite increased adiponectin expression in the skeletal muscle, patients with CHF are characterized by downregulation of AdipoR1 that is most probably linked to deactivation of the PPAR-␣/AMP-activated protein kinase pathway. These facts suggest functional adiponectin resistance at the level of the skeletal muscle in CHF. (Circ Heart Fail. 2010;3:185-194.)

Adipokines and cardiovascular disease: A comprehensive review

“…Despite the cardioprotective effects of adiponectin, there have also been described diseases and conditions which correlate positively with levels of adiponectin. Interesting is the demonstration of elevated levels of adiponectin in patients with chronic heart failure 92,80 . Several explanations for this have been offered and one of them could be resistance to adiponectin 92 .…”

“…Interesting is the demonstration of elevated levels of adiponectin in patients with chronic heart failure 92,80 . Several explanations for this have been offered and one of them could be resistance to adiponectin 92 . In patients with chronic heart failure ANP expression is increased in skeletal muscle and by deactivation of the PPAR/AMP signal the expression of AdipoR1 is lowered.…”

Increased Levels of Retinol Binding Protein 4 in Patients With Advanced Heart Failure Correct After Hemodynamic Improvement Through Ventricular Assist Device Placement

“…1 The development of IR in heart failure is likely multi-factorial, and the result of various hemodynamic and hormonal changes influencing differential expression of pro-inflammatory and anti-inflammatory mediators and adipocytokines, including tumor necrosis factor (TNF)-α, leptin, resistin and adiponectin. [2][3][4][5] Retinol binding protein 4 (RBP4) is an adipocytokine that mediates the transport of retinol from the liver to various target tissues. It is synthesized and stored in both hepatocytes and adipocytes and its expression is increased in adipose tissue that has reduced expression of the glucose transporter-4.…”

The relationship between adiponectin, NT-pro-BNP and left ventricular ejection fraction in non-cachectic patients with systolic heart failure: an observational study

“…Elevated Adp levels may compensate a state of impaired energy metabolic efficacy (a progressive shift from fatty acid utilization to glucose utilization) and malnutrition (15). Hence, functional adiponectin resistance has been observed in the skeletal muscle of patients with chronic HF (16). This would explain why, despite known cardiac and vascular protective effects (4).…”