White adipose tissue (WAT) is the principal site for lipid accumulation. Males and females maintain distinctive WAT distribution patterns. Specifically, males tend to accumulate relatively more visceral fat whereas females accumulate relatively more subcutaneous fat. The phenomenon of maintaining typical sex-specific fat distributions suggests sex-specific mechanisms that regulate energy balance and adiposity. We used two distinct approaches to reduce fat mass, caloric restriction (CR) and surgical fat removal (termed lipectomy), and assessed parameters involved in the regulation of energy balance. We found that male and female mice responded differentially to caloric restriction (CR)- and to lipectomy-induced fat loss. Females decreased energy expenditure during CR or after lipectomy. In contrast, males responded by eating more food during food return following CR or after lipectomy. Female CR mice conserved subcutaneous fat whereas CR males lost adiposity equally in the subcutaneous and visceral depots. In addition, female mice had a reduced capability to restore visceral fat following fat loss. Following CR, plasma leptin levels decreased in male but not female mice. The failure to increase food intake after returning to ad libitum intake in females could be due to the relatively stable levels of leptin. In summary, we have found sexual dimorphisms in the response to fat loss that point to important underlying differences in the strategies by which male and female mice regulate body weight.