Shankar and Colleagues Describe Drug to Reduce Fatty Liver Disease

New research findings by Kripa Shankar, Ph.D., and colleagues, reported in Molecular Metabolism, could lead to a treatment for metabolic dysfunction-associated fatty liver disease (MAFLD), obesity, and high cholesterol.

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

Why is this research noteworthy?

Our research demonstrating that a long-acting analog of the hormone LEAP2 reduces fattiness and inflammation in the liver, causes marked weight loss, and lowers cholesterol levels in mice is noteworthy because it suggests that this class of compounds can be used as a new treatment for fatty liver disease and obesity.

What are the top takeaways from the research?

1. Administration of the LEAP2 analog markedly improved several facets of MAFLD, including hepatic steatosis, inflammation, high-grade fibrosis, and transaminitis. 
2. Administration of the LEAP2 analog also prominently reduced body weight & lowered plasma cholesterol.
3. In contrast, experimental genetic deletion of the gene that encodes the hormone LEAP2 led to slight worsening of some of these parameters.

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 LEAP2-KO mice exhibited greater sensitivity to the so-called “hunger hormone” ghrelin. Additionally, when we previously placed female LEAP2-KO mice on a Western-style 42% high-fat diet, they exhibited lower energy expenditure and locomotor activity but higher food intake, leading to a greater body weight gain, lean mass, and body length. Also, in collaborative studies with the Du lab at University of Kansas, we helped to show that lowering LEAP2 levels in elderly mice improved cognitive performance (memory).

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 and Novo Nordisk Research Center Indianapolis. Funding for the UT Southwestern Small Animal Imaging Resource (UT-SAIR) was provided by the Cancer Prevention and Research Institute of Texas.  

How does this research advance the field?

This study represents the first investigation into the effects of both LEAP2 deletion and LEAP2 analog administration in a MAFLD mouse model, offering valuable insights into the role of LEAP2 in MAFLD and obesity. Additionally, our findings of prominent effects of a novel long-acting LEAP2 analog contribute significantly to the advancement of therapeutic interventions targeting metabolic diseases. Notably, our findings demonstrate substantial efficacy of LA-LEAP2 in reducing body weight and hepatic steatosis, highlighting its therapeutic potential in addressing MAFLD and obesity.

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

Our studies reveal marked effects for the novel LEAP2 analog to improve MAFLD and reduce body weight, with additional marked improvements in lipid profiles in preclinical models. We hope that these can be translated into new, effective therapies for individuals with MAFLD, obesity, and dyslipidemia.

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

This research was conducted within UT Southwestern’s Center for Hypothalamic Research, which was established in 2006 to bring together scientists interested in understanding the mechanisms by which the hypothalamus regulates eating, body weight, blood glucose, and related metabolic processes. The Center is unique among academic institutions in that it is the only one with a primary focus on the hypothalamus. By studying the hypothalamus plus interconnected brain regions, peripheral organ systems such as the pancreatic islets, and hormonal networks along the gut-brain axis, we hope to better understand the pathogenesis of obesity, diabetes, and related metabolic/mood disorders. 

This research also is aligned with the UT Southwestern’s Nutrition and Obesity Research Center’s mission to support 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.

Further, this research has been facilitated by the mission of the Division of Endocrinology at UT Southwestern, with its diverse faculty whose expertise spans the spectrum of endocrine diseases, including obesity and diabetes.

 

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.