In nonalcoholic fatty liver disease (NAFLD), excess fat builds up in the liver. There are no existing treatments for NAFLD, so without changes to a person’s diet or exercise, this condition can lead to chronic liver inflammation and damage known as non-alcoholic steatohepatitis (NASH).

Researchers at Rutgers University reported that mice fed a high-fat diet (HFD) were better protected from developing NASH when they made more of a hormone, kisspeptin (named after Hershey’s kisses), which regulates sex and metabolism (1,2). This result, which was published in The Journal of Clinical Investigation, suggests that the kisspeptin receptor, KISS1R, may offer a therapeutic target for NASH.

“NASH is the leading cause of liver transplant in the US. Up to [12%] of the patients can develop liver cell carcinoma or hepatocellular carcinoma, which is the fastest rising cancer in the US right now. And the prognosis is very dismal,” said Moshmi Bhattacharya, a molecular biologist at Rutgers University who led the study. 

Prior studies, including one by Mehboob Hussain, an endocrinologist at the University of Michigan, showed that kisspeptin is expressed in the liver, but researchers had no idea what it does there (3). “Before that, kisspeptin was known to regulate fertility and puberty. Nobody had known that kisspeptin was expressed in the liver at that time, and that essentially opened up the field into looking more closely at kisspeptin as a metabolic hormone,” said Hussain, who was not involved in this new study. 

To investigate the role of kisspeptin in liver metabolism, Bhattacharya and her team developed a mouse model lacking the kisspeptin gene, Kiss1r, in the liver, but still expressing it normally in the rest of the body. According to Stephania Guzman, a graduate student in Bhattacharya’s lab and coauthor of the paper, their data revealed “a striking difference” between the Kiss1r   knockout and control mice in fat metabolism in the liver. 

The researchers discovered that the KISS1R signaling pathway in the liver activates an energy regulator called 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK), which inhibits liver lipid synthesis and fibrosis. They found that injecting a kisspeptin analog into mice fed an HFD and lacking AMPK in the liver, led to a decrease in the ability to metabolize fat and fend off NASH. “This solidified to us that AMPK is a really important regulator through which kisspeptin and its receptors are acting,” Guzman said.

Manuel Tena-Sempere, a neuroendocrinologist at the University of Córdoba who was not involved in the study, was impressed with the authors’ decision to use a Kiss1r   knockout mouse for their preclinical research. 

“One of the main challenges [of conducting this type of study] is the difficulty to tease apart the reproductive and metabolic functions of kisspeptin,” he said. Since both reproductive and metabolic functions are interconnected, altering the level of kisspeptin in one system could cause an indirect effect on the other. One example of this is the increase in both estradiol level (a sex hormone) and thermogenesis (energy production) in mice injected with kisspeptin (4). 

The approach taken in this paper is “very elegant,” said Tena-Sempere. Because the kisspeptin receptor is specifically removed from the liver of the mice, “there should be a targeted action specifically in the liver that is not affecting other components such as the reproductive system,” he said.

While the results are promising, Bhattacharya interpreted them with caution. “What happens in mice may not happen in humans,” she said. 

In the future, Bhattacharya would like to test whether the effects of kisspeptin they observed in their mouse model translate to humans in a clinical trial setting.

Overall, “[the researchers] provide quite convincing evidence that if you do not have kisspeptin signaling in the liver, your liver is prone to accumulate lipids, leading to non-alcoholic fatty liver disease, which is a very common condition in obese patients,” said Tena-Sempere. Because of this, he believes that the study demonstrates “a really important phenomenon in terms of translational medicine.” 

References 

1. Dhillo, W. Timeline: kisspeptins. Lancet Diabetes Endocrinol  1, 12-13 (2013).
2. Guzman, S. et al. Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model. J Clin Invest  132, e145889 (2022).
3. Song, W. et al. Glucagon Regulates Hepatic Kisspeptin to Impair Insulin Secretion. Cell Metabolism  19, 667-681 (2014).
4. Sobrino, V. et al. Kisspeptins and the neuroendocrine control of reproduction: Recent progress and new frontiers in kisspeptin research.” Front Neuroendocrinol  65, 100977 (2022).