Objective: Protein leverage plays a role in driving increased energy intakes that may promote weight gain. The influence of the protein to carbohydrate ratio (P:C) in diets of C57BL/6J mice on total energy intake, fat storage, and thermogenesis was investigated., Design and Methods: Male mice (9 weeks old) were provided ad libitum access to one of five isocaloric diets that differed in P:C. Food intake was recorded for 12 weeks. After 16 weeks, white adipose tissue (WAT) and brown adipose tissue (BAT) deposits were dissected, weighed, and the expression levels of key metabolic regulators were determined in BAT. In a separate cohort, body surface temperature was measured in response to 25 diets differing in protein, fat, and carbohydrate content., Results: Mice on low P:C diets (9:72 and 17:64) had greater total energy intake and increased WAT and BAT stores. Body surface temperature increased with total energy intake and with protein, fat, and carbohydrate, making similar contributions per kJ ingested. Expression of three key regulators of thermogenesis were downregulated in BAT in mice on the lowest P:C diet., Conclusions: Low-protein diets induced sustained hyperphagia and a generalized expansion of fat stores. Increased body surface temperature on low P:C diets was consistent with diet-induced thermogenesis (DIT) as a means to dissipate excess ingested energy on such diets, although this was not sufficient to prevent development of increased adiposity. Whether BAT was involved in DIT is not clear. Increased BAT mass on low P:C diets might suggest so, but patterns of thermogenic gene expression do not support a role for BAT in DIT, although they might reflect failure of thermogenic function with prolonged exposure to a low P:C diet., (Copyright © 2012 The Obesity Society.)