The looming pandemic of obesity and overweight, driven by ready access to high-calorie food and an increasingly sedentary way of life, poses a severe threat to global public health. The pathological accumulation of excess dysfunctional adipose tissue that characterizes obesity is a major risk factor for many other diseases, including type 2 diabetes, cardiovascular disease, hypertension, stroke, arthritis, and various types of cancer (1). A basic, but often misunderstood, concept is that weight gain is caused by a fundamental energy imbalance, when energy intake from food chronically exceeds energy expended by physical activity and metabolic processes (Fig. 1). Humans have evolved efficient biological mechanisms to acquire and defend their energy stores. A therapy for weight loss must, therefore, involve a decrease in food intake and/or an increase in energy expenditure.

In addition to the better-known white adipose tissue that specializes in lipid storage and undergoes pathological expansion during obesity, mammals are also equipped with thermogenic brown adipose tissue (BAT). BAT evolved in mammals to dissipate large amounts of chemical energy as heat. Brown fat cells possess large numbers of mitochondria that contain a unique protein called uncoupling protein 1 (UCP1). UCP1 functions to dissipate the proton motive force that is normally used to drive the synthesis of cellular ATP (2). As a consequence of UCP1 action, the energy in the mitochondrial electrochemical gradient is released in the form of heat. Indeed, BAT is a key thermogenic tissue in rodents and other small mammals, including newborn humans, that defends core body temperature in cold weather. The sensation of cold causes sympathetic nerves to release catecholamines in BAT that stimulate proliferation and heat production by brown fat cells (2). Studies in rodents have also unequivocally demonstrated that BAT plays an essential role in energy balance and that its activity profoundly influences body weight (3). Though BAT persists as a distinct tissue in small mammals, the major deposit of BAT in newborn humans (between the shoulder blades) regresses shortly after birth. Other depots of BAT have been known to exist in adult humans for many decades; however, estimates of