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The AMP-activated protein kinase (AMPK) is an αβγ heterotrimer that regulates appetite and fuel metabolism. We have generated AMPK β1-/- mice on a C57Bl/6 background that are viable, fertile, survived greater than 2 years, and display no visible brain developmental defects. These mice have a 90% reduction in hepatic AMPK activity due to loss of the catalytic a subunits, with modest reductions of activity detected in the hypothalamus and white adipose tissue and no change in skeletal muscle or heart. On a low fat or an obesity-inducing high fat diet, β1-/- mice had reduced food intake, reduced adiposity, and reduced total body mass. Metabolic rate, physical activity, adipose tissue lipolysis, and lipogenesis were similar to wild type littermates. The reduced appetite and body mass of β1-/- mice were associated with protection from high fat diet-induced hyperinsulinemia, hepatic steatosis, and insulin resistance. We demonstrate that the loss of β1 reduces food intake and protects against the deleterious effects of an obesity-inducing diet. [ABSTRACT FROM AUTHOR]