Leptin is known to be an important element to link food intake, energy expenditure, and body composition. Leptin may act on skeletal muscle metabolism through two pathways. One is a direct action on the leptin receptor expressing in the skeletal muscle. Plasma leptin concentrations are positively correlated with muscle mass, whereas ob/ob and db/db mice, which are impaired with leptin signaling, exhibit less muscle mass. The other is that leptin signaling in the hypothalamus activates β2-adrenoceptor signaling, resulting in increased mass in skeletal muscle. Previous studies demonstrated that β2-adrenergic agonists stimulate skeletal muscle to enhance muscle anabolism and mass. Epac (exchange protein directly activated by cAMP) 2a-knockout (KO) mice are demonstrated to exhibit an acceleration of high fat diet-induced obesity with hypothalamic leptin resistance. When fed with normal chow diet, however, the KO mice only appeared to have increased adipocyte size and plasma leptin levels, but with normal body weight, food intake, and glucose and insulin sensitivity. Therefore, it may be plausible that KO mice are in an intermediate state that is subnormal between normal and overtly abnormal leptin sensitivity in the hypothalamus. Reconfirmed that the two tissues would not express Epac2a, KO mice showed greater protein expression of myogenin in skeletal muscle and UCP-1 in brown adipose tissue. They had greater basal energy expenditure and resistance to dexamethasone-induced muscle atrophy and endurance to cold stress. In wild type mice, intraperitoneal leptin administration mimicked the responses of KO mice to dexamethasone and cold stress. Taken together, it supports hypothesis that loss-of-function of Epac2a with hyperleptinemia and mild leptin resistance may be influential to body energy metabolism in skeletal muscle and brown adipose tissue. It may be via their own