Targeting FFA1 and FFA4 receptors in cancer-induced cachexia

Abstract

Free fatty acid (FFA) receptors FFA1 and FFA4 are omega-3 molecular targets in metabolic diseases; however, their function in cancer cachexia remains unraveled. We assessed the role of FFA1 and FFA4 receptors in the mouse model of cachexia induced by Lewis lung carcinoma (LLC) cell implantation. Naturally-occurring ligands α-linolenic acid (ALA) and docosahexaenoic acid (DHA), the synthetic FFA1/FFA4 agonists GW9508 and TUG891, or the selective FFA1 GW1100 or FFA4 AH7614 antagonists were tested. FFA1 and FFA4 expression and other cachexia-related parameters were evaluated. GW9508 and TUG891 decreased tumor weight in LLC-bearing mice. Regarding cachexia-related endpoints, ALA, DHA, and the preferential FFA1 agonist GW9508 rescued body weight loss. Skeletal muscle mass was reestablished by ALA treatment, but this was not reflected in the fiber cross-sectional areas (CSA) measurement. Otherwise, TUG891, GW1100, or AH7614 reduced the muscle fiber CSA. Treatments with ALA, GW9508, GW1100, or AH7614 restored WAT depletion. As for inflammatory outcomes, ALA improved anemia, while GW9508 reduced splenomegaly. Concerning behavioral impairments, ALA and GW9508 rescued locomotor activity, while ALA improved motor coordination. Additionally, DHA improved grip strength. Notably, GW9508 restored abnormal brain glucose metabolism in different brain regions. The GW9508 treatment increased leptin levels, without altering UCP-1 downregulation in visceral fat. LLC-cachectic mice displayed FFA1 upregulation in subcutaneous fat, but not in visceral fat or gastrocnemius muscle, while FFA4 was unaltered. Overall, the present study shed new light on FFA1 and FFA4 receptors' role in metabolic disorders, indicating FFA1 receptor agonism as a promising strategy in mitigating cancer cachexia.

Cancer-Related Cachexia: The Vicious Circle between Inflammatory Cytokines, Skeletal Muscle, Lipid Metabolism and the Possible Role of Physical Training

“…The synthetic agonists GW9508 and TUG891 and the natural ligands ALA and DHA (α-linolenic acid and docosahexaenoic acid) of the free fatty acid receptors FFA1 and FFA4 showed a reduction in tumor weight and weight loss in LLC-bearing mice. A healthy effect on adipose tissue was also achieved by treatments with the selective FFA1 and FFA4 antagonists (GW1100 and AH7614, respectively) [ 67 ].…”

Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer

“…Omega-3 PUFA supplementation has been suggested for the treatment of cancer-related cachexia symptoms [ 14 , 16 , 43 ]. The absorption and metabolism of omega-3 PUFAs found in fish oils, such as eicosapentaenoic acid or docosahexaenoic acid, are theorized to improve cachexia by inhibiting proteolysis, lipolysis, and nuclear factor kappa B-induced inflammation [ 14 , 16 , 44 ].…”

A Free Fatty Acid Synthetic Agonist Accelerates Wound Healing and Improves Scar Quality in Mice

“…Therefore, we found it interesting to evaluate the expression of these 2 receptors in the skin. In addition, we compared it with the expression in other organs involved in metabolism, because in these tissues, the beneficial effects of its activation are already well established (Engel et al, 2020; Freitas et al, 2020; Hirasawa et al, 2005). Thus, the rationale for this study was that, if these receptors are expressed in the skin in a similar amount to that in other tissues, perhaps activation in the skin could lead to desired effects on wound healing.…”

“…It was previously shown that FFAR1 functions primarily in insulin secretion in pancreatic beta cells (Alquier et al, 2009); in addition, it is expressed in the anorexigenic POMC neurons and is involved in the regulation of food intake and energy expenditure (Dragano et al, 2017). FFAR4 is highly expressed in adipose tissue, and the use of GW9508 was shown to restore white adipose tissue depletion in a model of cancer-induced cachexia (Freitas et al, 2020). FFAR4 is the most studied protein of the 2 receptors evaluated in the current investigation.…”