The present invention relates to AMPK activation utilizing phytochemicals, natural plant extracts and combinations. Disclosed are methods, compounds, and compositions comprising drugs, medical foods, and dietary supplements for the prevention and treatment of metabolic disorders, in particular obesity, weight gain, insulin resistance syndromes, diabetes, fasting hyperlipidemia and osteoarthritis. More specifically, the invention relates to pharmaceutical therapeutic methods and compositions utilizing phytochemicals, natural plant extracts and combinations to modify myocyte, hepatocyte, adipocyte, cardiac or pancreatic physiology through activation of AMPK.