Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) causes dramatic reductions in white adipose tissue in mice but has had limited effectiveness in humans. Determination of the signaling pathways involved may lead to better regulation of adiposity. T10c12 CLA was found to activate AMP-activating protein kinase (AMPK), a central regulator of cell metabolism. Compound C, a potent inhibitor of AMPK, prevents many of the typical responses to treatments with t10c12 CLA including the integrated stress response (ISR), the inflammatory response, the reduction in key lipogenic transcription factors, and delipidation. Treatment of adipocytes or mice with t10c12 CLA in conjunction with AMPK activator metformin results in more delipidation than treatment with the individual chemicals. Additionally, the combination showed a reduced inflammatory response relative to a t10c12 CLA treatment alone. The combination of t10c12 CLA and metformin, widely used to treat insulin resistance and Type II diabetes, has potential as a treatment for reducing adiposity in humans.