Combined AMPK activation and ghrelin ameliorate cancer cachexia through complementary effects on energy homeostasis, inflammation, and wasting

BackgroundCancer-associated cachexia is characterized by progressive loss of skeletal muscle and adipose tissue driven by systemic inflammation and metabolic dysregulation. AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, but its role in cachexia and its therapeutic potential remains incompletely defined. We investigated AMPK signaling during cachexia and whether pharmacological AMPK activation alone or combined with ghrelin could ameliorate disease manifestations. MethodsCachexia was induced in male C57BL/6 mice by Lewis lung carcinoma (LLC) implantation. Additional models included fibrosarcoma (CHX and MN/MCA1) and chronic lymphocytic choriomeningitis virus (LCMV) infection. AMPK was activated using AICAR and BC1618 (AB), alone or combined with ghrelin (AB+G). Metabolic, inflammatory, and functional outcomes were assessed in hypothalamus, skeletal muscle, adipose tissue, and serum. ResultsLLC-bearing mice developed cachexia characterized by reduced body weight, lean and fat mass, hypophagia, and elevated circulating IL-6 and corticosterone. Cachectic LLC mice displayed increased Il6 and Il1{beta} expression in hypothalamus, skeletal muscle, and white adipose tissue (WAT). Furthermore, AMPK activation failed to increase in hypothalamus or peripheral tissues despite profound energy deficit. A similar defect in AMPK responsiveness was observed in CHX and LCMV models, indicating a conserved feature of cachexia. AB treatment in LLC mice reduced circulating IL-6 and corticosterone levels and decreased skeletal muscle atrogene expression and IL-6/STAT3 signaling, partially preserving muscle mass, fiber size, and grip strength. However, food intake remained low, and WAT was largely unresponsive, maintaining elevated Il6 expression and tissue loss. Ghrelin alone increased food intake in LLC mice but did not ameliorate the cachectic phenotype. In contrast, AB+G restored food intake and prevented loss of lean and fat mass. LLC AB+G mice exhibited reduced hypothalamic Il6 and serotonin transporter (Slc6a4) expression, normalized adipocyte morphology and serum leptin levels, decreased adipose Il6 and Atgl expression and reduced WAT sympathetic innervation. AB+G further lowered circulating corticosterone levels, and provided greater protection against muscle wasting, with increased Pgc1 expression and improved muscle function. Neither intervention affected tumor growth or tumor inflammatory gene expression. ConclusionsCancer cachexia is associated with a central and peripheral failure to appropriately activate AMPK signaling in response to the energetic stress imposed by cachexia. Combined AMPK activation and ghrelin administration exerted complementary effects on energy homeostasis, inflammation, and tissue wasting, resulting in greater protection against cachexia than either intervention alone. These findings support combined AMPK-ghrelin targeting as a promising therapeutic strategy for cancer cachexia.