Raising adiponectin levels (right) reduces the formation of liver tumors in male mice. [Manieri et al., 2019]

Researchers in Spain have discovered a potential mechanism that may explain why liver cancer is more common in men than it is in women. Studies by Guadalupe Sabio PhD, at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, found that the hormone adiponectin, which is produced by fat cells, is expressed at higher levels in women than it is in men or in obese people, who are also at an increased risk of liver cancer. Studies in rodent models indicated that adiponectin protects against the growth of hepatocellular carcinoma (HCC) by activating two anticancer proteins in liver cells, but in adult males adiponectin production is suppressed by the actions of testosterone on another protein, which lowers the level of protection against cancer.

The findings also point to new potential strategies for treating HCC. “One approach would be to use adiponectin itself, while another option is metformin, a drug used to treat diabetes that targets the same anticancer protein as adiponectin,” Sabio stated. The researchers report their findings in the Journal of Experimental Medicine, in a paper titled, “Adiponectin accounts for gender differences in hepatocellular carcinoma incidence.”

HCC is the sixth most common cancer type and the fourth leading cause of cancer-related death worldwide, the authors wrote. Incidence of the disease is on the increase due to the rise in obesity, but treatment options are limited, and once diagnosed, survival is poor. “Better preventive, diagnostic, and therapeutic tools are therefore urgently needed, particularly in view of the important contribution of obesity to HCC incidence worldwide.” Epidemiological studies have also shown that HCC is more common in men than in women, with research in mouse models indicating that male animals are at a higher risk of developing the disease than are females.

The adipokine adiponectin, which is produced by adipocytes, is believed to play a protective role in cancer, but is found in higher amounts in women, than in men, although, as the authors commented, “Its role in HCC is controversial and requires further investigation.” Nevertheless, Sabio stated, “… circulating levels of adiponectin decline with the development of obesity and after puberty in men, and these are precisely the populations with higher rates of liver cancer. This observation prompted us to study the phenomenon in depth.”

The team’s studies first confirmed that adiponectin levels were higher in healthy women than they were in men. The researchers then showed that circulating levels of the hormone were also twice as high in healthy female laboratory mice than in male mice, and appeared to protect the female animals against the development of HCC tumors specifically. While implanted HCC tumor cells grew more strongly in the male mice than in the female animals, there was no gender difference in the growth of colon- or menalmona-derived tumor cells.

Working in collaboration with Elisa Manieri PhD, and Leticia Herrera-Melle PhD, the researchers showed that differences in adiponectin levels appeared to be related to male hormone levels. Castrated male mice exhibited similar adiponectin levels to those found in females, and they also developed smaller tumors than uncastrated male mice. Male and female animals that were genetically engineered to lack adiponectin (knockout, or KO mice) also developed similar sized tumors.

Herrera-Melle commented that to understand the mechanism through which fat controls the growth of tumors in the liver, “we focused on the effect of testosterone on adipose tissue. These studies showed that testosterone reduces the amount of adiponectin released to the circulation.”

The protective effects of adiponectin were also observed in a chemically induced model of HCC that was engineered to overexpress the adipokine, “indicating that adiponectin reduces tumor progression and may be a potential treatment for HCC,” the team noted.

The image on the left is the control of the males, and on the right is of the males with the highest levels of adiponectin. [CNIC]
Previous work in rodents had shown that adiponectin activates the p38 MAPK and AMPK pathways in the liver. p38α had been found to suppress liver cancer cell development by reducing cell proliferation, so that mice deficient in p38α in the liver exhibited increased tumor development. Prior studies have also indicated that AMPK suppresses cancer, the authors reported, and it has been suggested that the AMPK activator metformin, which is used to treat type 2 diabetes, may also improve survival among liver cancer patients. “Consequently, AMPK is emerging as an important metabolic tumor suppressor and a promising target for cancer prevention and therapy,” they commented.

The latest studies by Sabio et al in male and female rodents indicated that adiponectin activates p38α and AMPK in liver cells, which act to block cell proliferation and tumor growth. They also demonstrated that testosterone in the male animals activated the protein JNK1 in fat cells, which inhibited adiponectin production. “Adipose tissue JNK activation was significantly reduced in castrated males, whereas testosterone injection was enough to increase its activation to noncastrated mice levels,” they noted.

The authors concluded that their study demonstrates that adiponectin plays an important role in protecting female mice against HCC by activating p38α and AMPK. “These results indicate that activation of JNK in adipose tissue inhibits adiponectin secretion, promoting tumor growth in males … This study provides insight into adipose tissue to liver crosstalk and its gender relation during cancer development, having the potential to guide strategies for new cancer therapeutics … Our results suggest that adiponectin and metformin could be of use in the treatment of HCC.”

 

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