Mouse engineered to lack adipose triglyceride lipase are resistant to tumor-related fat and muscle loss.

Scientists suggest that blocking an enzyme involved in fat breakdown could represent a new approach to preventing the wasting syndrome called cachexia in cancer patients.  They have shown that mice lacking the gene for adipose triglyceride lipase (Atgl) were more resistant to tumor-related white adipose tissue (WAT) lipolysis, myocyte apoptosis, and proteasomal muscle degradation. The mice also maintained normal adipose and gastrocneumius muscle mass.

Upregulation of ATGL activity was in addition found in autopsy samples from cancer patients with cachexia, with the level of ATGL activity correlating inversely with body mass. The team at the Medical University of Graz and Graz University of Technology in Austria report their findings in Science Express in a paper titled “Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia.”

Cancer-associated cachexia (CAC) is thought to be a distinct tumor-associated metabolic condition that specifically targets adipose tissue and muscle. The breakdown of fat requires lipolysis of triacylglycerol (TG), which is mediated by ATGL and hormone-sensitive lipase (HSL).

Previous studies have in addition shown that severe lipid loss in CAC is driven by changes in lipid catabolism, and the condition is associated with increased plasma levels of fatty acids and glycerol as well as increased expression of lipid mobilizing factors. The researchers therefore postulated that the disruption of fat catabolism might prevent the initiation and/or progression of CAC.

The team carried out studies in two different cachexia mouse models, which lacked either Atgl or Hsl. Wild-type mice and the Atgl and Hsl gene knockouts were administered with lung cancer or melanoma cells to induce cachexia. The resulting tumor weights in the three mouse models were statistically similar, although, tended to be lower in the Atgl and Hsl knockouts. Conversely, total body weight (after subtraction of tumor weight) differed drastically in lipase-deficient mouse models compared with the wild-type mice.

The wild-type mice injected with cancer cells started to lose weight after 14 days and demonstrated significant weight loss after three weeks. In contrast, the Atgl-knockouts were completely protected from weight loss and in fact weighed the same as wild-type mice without tumors throughout the course of the experiment.

Interestingly, the Hsl knockouts with cancer did lose some weight, but not as much as the cancer-bearing wild-type mice, suggesting that Hsl provided some protection from CAC. None of the differences in weight loss in response to tumors were related the amount of food intake.

“Thus, in the mouse, protection from CAC-associated weight loss can be entirely conferred by the lack of ATGL and partially by the absence of HSL,” the authors state.

In support of previous findings, plasma glucose, fatty acid, and TG levels were much lower in overnight-fasted Atgl knockouts, compared with wild-type mice. Again, Hsl-knockouts demonstrated FA and TG levels in between those of the Atgl knockouts and the normal wild-type animals.

And while WAT mass dropped significantly in tumor-bearing wild-type mice, neither tumor type affected the WAT mass of Atgl-knockouts. Rather, the weight of body fat depots and total body fat actually increased in these animals when compared with wild-type mice without tumors.

As expected, the tumor-bearing Hsl-knockouts lost some WAT but not as much as the wild-type mice with cancer. All these findings held true independent of feeding status. In further support of the increase in WAT lipolysis, the researchers in addition determined that the release of fatty acids and glycerol from WAT was increased in cancer-bearing wild-type mice but not in Atgl-knockouts and was attenuated in the tumor-bearing Hsl knockouts.

Interestingly, each mouse genotype displayed elevated levels of TNF-α, IL-6 l, and ZAG in response to cancer growth.“ This suggests that in wild-type mice the increased concentrations of inflammatory and lipolytic agonists induce lipolysis via ATGL and HSL, leading to the uncontrolled loss of WAT and cachexia,” the researchers note.  “In the absence of lipases, particularly in the absence of ATGL, this process is disrupted and WAT is retained.”

In human cancer patients CAC leads to loss of skeletal and cardiac muscle as well as fat tissue, and in wild-type mice tumor growth was associated with lower skeletal muscle mass and heart weight. These animals also demonstrated significant loss in weight of the gastrocnemius muscle in the calf, which was associated with a reduction in total muscle protein. Atgl-knockouts, however, suffered no significant loss in weight of this muscle in response to tumors. The Hsl-knockouts did lose some gastrocnemius muscle weight but not as much as the wild-type animals.

Gastrocnemius muscle loss in wild-type and Hsl-knockouts was associated with increases in muscle proteasome activity and apoptosis-related caspase activity, and also with increased fatty acid oxidation. This latter feature was associated with increased mRNA expression levels of genes involved in the regulation of cellular fatty acid uptake, fatty acid transport into mitochondria, and mitochondrial function. “This suggests that the catabolic state in CAC mobilizes FA from adipose tissue leading to an energy substrate switch from glucose to fatty acid utilization in skeletal muscle,” the researchers remark.

In a final set of tests the researchers assessed ATGL and HSL-mediated TG hydrolase activities in visceral WAT taken from autopsy samples of 27 patients, 12 of whom had died from cancer. Of these 12, six had suffered cachexia.

The analyses confirmed that toal lipase, ATGL, and HSL activities were significantly higher in visceral WAT of cancer patients compared with individuals without cancer and were significantly higher in cancer patients with cachexia compared with cancer patients without cachexia. Lipase activities in cancer patients without cachexia were similar as those of non-cancer patients. Significantly, a significant inverse correlation was found between total lipase, ATGL and HSL activities in the WAT of cancer patients and their body mass index, but no correlation was found in the noncancer patients.

“In summary, our data are consistent with the view that lipolysis plays an instrumental role in the pathogenesis of CAC,” the researchers conclude. “Pharmacological inhibition of lipases may represent a powerful strategy to avoid the devastating condition of cachexia in response to cancer or other chronic diseases.”

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