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Obesity occurs when energy consumption (from food) chronically exceeds energy expenditure, and this dramatically increases the risk of developing many life- threatening diseases. Adipose tissues, which consist mainly of adipocytes, are important in regulating systemic energy levels. Two general classes of adipocytes are found in mammals: white and brown. Whereas white adipocytes store and release energy in the form of fatty acids in response to systemic demands, brown adipocytes burn substrates, including fatty acids and glucose, to produce heat in response to various stimuli; this process is known as adaptive non-shivering thermogenesis.
The thermogenic activity of brown fat cells relies, to a great extent, on uncoupling protein 1 (UCP1), a protein that is localized on the inner membrane of mitochondria. When activated, UCP1 catalyses the leak of protons across the mitochondrial membrane1, which uncouples oxidative respiration from ATP synthesis; the resulting energy derived from substrate oxidation is dissipated as heat (BOX1).
Brown adipose tissue (BAT) in infants and adults is organized into discrete depots that are specialized for the efficient production and distribution of heat. BAT is densely innervated by the sympathetic nervous system and, in many cases, nerve fibres directly synapse onto brown adipocytes. Cold, which is sensed by the central nervous system, stimulates sympathetic outflow to BAT, and noradrenaline secreted by nerve fibres interacts with
adrenergic receptors on brown adipocytes to activate thermogenesis2. BAT is also very highly vascularized, which enables substrates and oxygen to be delivered to brown adipocytes for thermogenesis and enables the resultant heat to be distributed to the rest of thebody3.
UCP1-expressing and mitochondrial-rich adipocytes also develop in white adipose tissue (WAT) depots in response to cold exposure and certain other stimuli4, and these induced adipocytes have consequently been called beige or brite (brown-in-white) adipocytes. Beige fat is defined as the clusters of UCP1-expressing adipocytes that reside outside traditional brown fat depots. Like brown adipocytes, beige adipocytes have the capacity to convert energy intoheat4.
Brown and beige fat are major sites of adaptive thermogenesis in mice, and the activity of these tissues can significantly contribute to whole-body energy expenditure. In humans, BAT was previously thought to exist in meaningful amounts only in infants and to regress and become metabolically inconsequential in adults....