The concept of dual-adaptive thermogenesis underlying metabolic adaptation to prolonged energy deficit posits that there are two control systems that govern energy sparing: a rapid-reacting system to energy deficit and a slow-reacting system to fat store depletion. The latter control system, referred to as the "adipose-specific" control of thermogenesis, contributes to accelerating fat store replenishment (catch-up fat) during weight regain. The case is put forward here that, whereas adaptive thermogenesis during weight loss results primarily from central suppression of the sympathetic nervous system and hypothalamic-pituitary-thyroid axis, during weight regain it operates primarily through peripheral tissue resistance to the actions of this neurohormonal network. Emerging evidence that altered deiodination of thyroid hormones within the skeletal muscle and liver is a key determinant of such peripheral resistance therefore offers entry points toward elucidating the molecular mechanisms that underlie the adipose-specific control of thermogenesis and unraveling tissue-specific targets to counter obesity recidivism.