Nearly one third of cancer deaths may be attributed to cachexia. Factors that contribute to this unintended weight loss include anorexia, deranged energy metabolism, and elevated inflammation. While the loss of skeletal muscle mass predicts for poor prognosis and reduced quality of life, it is the loss of adipose tissue that is the strongst predictor for mortality in patients with cachexia. Because of the strong relationship of adipose loss with mortality, and because adipose mass declines early in the pathogenesis of cancer cachexia, mitigating adipose loss could be a useful strategy for slowing the progression of cachexia. In mice, tumor-induced loss of adipose mass occurs coincident with loss of adipocyte function including an inability to store lipid and to secrete adipokines. The adipokine, adiponectin, may be of great importance since it is known to modulate inflammation and metabolism. In a mouse model of cancer cachexia, adiponectin decreases in a time dependent manner. Importantly for cachexia, adiponectin decreases inflammation, improves insulin sensitivity and increases b-oxidation through mitochondrial biogenesis in skeletal muscle. Our central hypothesis is that loss of adiponectin is a key driver of the pathogenesis of cancer cachexia.
In Aim #1, we will examine the ability of adiponectin to alter physiologic and metabolic aspects of cancer cachexia.
In Aim #2, we will determine the effect of adiponectin on biomarkers of skeletal muscle regeneration in mice with cancer cachexia. Effective therapies for treating cancer cachexia are lacking. Research outlined in this proposal is significant because it will probe the role of adiponectin, a cytokine that decreases inflammation and modulates metabolism, the loss of which is a driver of muscle loss. These studies should provide a mechanistic link between the loss of adipose tissue with the loss of muscle that contributes to mortality from cancer cachexia. Our long-term goal is to develop novel clinical treatments to improve functional status, quality of life, and survival for patients with cancer cachexia.
Cancer cachexia refers to rapid and unintended weight loss that results in diminished quality of life and reduce strength for withstanding cancer treatments. Given that: 1) there are largely ineffective therapies for this disorder, and 2) that obesity is actually a protective factor, there is a critical need to probe the relative relationship of adipos tissue as a key aspect of protecting patients from mortality. Our central hypothesis is that a cytokine derived from adipose tissue, so called adiponectin, is protective against the progression of cancer cachexia.
|Kliewer, Kara L; Ke, Jia-Yu; Tian, Min et al. (2015) Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. Cancer Biol Ther 16:886-97|