Zigman Lab Publishes Findings on Reducing Cancer-Related Cachexia

Cancer cachexia, a condition commonly seen in patients with advanced cancer, is marked by a decrease in food intake and significant weight loss due to the reduction of muscle mass and often fat tissue. A study published in Endocrinology by Salil Varshney, Ph.D., in the Zigman Lab, has demonstrated for the first time that reducing levels of the hormone LEAP2, which has been shown to reduce food intake and body weight, lessens the severity of cancer-related cachexia.

We asked Jeffrey Zigman, M.D., Ph.D., a Professor in the Center for Hypothalamic Research, to explain his team’s findings.

Why is this research noteworthy?

This research is noteworthy because it for the first time links changes in circulating levels of the hormone LEAP2 to severity of symptoms in individuals at risk to lose muscle mass and/or fat mass and reduce eating as a result of cancer.

What are the top takeaways from the research?

1. We demonstrate for the first time that reducing levels of the hormone LEAP2, which has been shown to reduce food intake and body weight, lessens manifestations of cancer-related cachexia-anorexia syndrome in experimental mouse models.
2. We confirm previous work suggesting that reducing signaling by the related hormone ghrelin, which has been shown to increase food intake and body weight, worsens manifestations of cancer-related cachexia-anorexia syndrome in experimental mouse models.
3. We also show that the presence of relatively lower blood levels of LEAP2 and higher blood levels of ghrelin in patients with cancer are associated with less weight loss in the preceding six months.

Does this build on previous findings from you or your lab, or other researchers at UTSW?

Yes – Previous work in the Zigman lab demonstrated that experimental mice which lack the hormone LEAP2 mice exhibit greater sensitivity to ghrelin and higher food intake, leading to a greater body weight gain, greater lean mass, and more advanced stages of metabolic dysfunction associated fatty liver disease (MAFLD). Also, in collaborative studies with the Du lab at University of Kansas, we previously helped to show that lowering LEAP2 levels in elderly mice improves cognitive performance (memory). Now, we have another example in which lowering LEAP2 shows efficacy in lessening cancer cachexia.

Are there any distinctive tools, technology, training, grants, development initiatives or state or federal funding such as NIH that deserve mentioning?

Funding for this study was provided by the NIH (R01DK103884 , R01AR067319, P30DK127984, and P30CA142543), the David and Teresa Disiere Foundation, and the U.S. Department of Veterans Affairs (BX002807). 

How does this research advance the field?

Altogether, these data suggest that less of the hormone LEAP2 with or without more of the hormone ghrelin results in a natural protective response against what would otherwise be even worsen loss of muscle mass and/or fat mass and even lower appetite in the setting of cancer cachexia. The finding that circulating levels LEAP2 can impact cancer cachexia disease severity had not previously been shown.

How does it tie into/advance toward clinical solutions for patients?

Our new data do suggest that using pharmacologic or other strategies to reduce circulating levels of LEAP2 could be implemented as a therapeutic strategy to improve cancer cachiexia outcomes.

How do UTSW’s education, clinical care, or other research missions tie into this research?

This research project links together actions of the related hormones LEAP2 and ghrelin, which act on the hypothalamus and other regions of the brain to affect food intake, body weight, adiposity, and muscle mass and function. It brought together resources from within UT Southwestern’s Center for Hypothalamic Research, Nutrition and Obesity Research Center, Simmons Comprehensive Cancer Center (SCCC), and the Division of Endocrinology. Of note, the Center for Hypothalamic Research brings together scientists interested in understanding the mechanisms by which the hypothalamus regulates eating, body weight, blood glucose, and related metabolic processes. The NORC supports research infrastructure, enrichment programs, and collaborative activities for investigators conducting research in the causal factors of nutrition and obesity-related health problems, including consequences, prevention, and alleviation. The SCCC’s mission is to ease the burden of cancer through ground-breaking discovery, transdisciplinary research, impactful community engagement, education, and exceptional patient care. The Division of Endocrinology includes faculty whose expertise spans the spectrum of endocrine diseases, including obesity, diabetes, and other metabolic disorders.

 

Dr. Zigman holds the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D.; the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; and the Diana and Richard C. Strauss Professorship in Biomedical Research.

To learn more about Dr. Zigman’s research, visit the Zigman Lab site.