Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

Exposure to cold drives IL-4-mediated alternative macrophage activation and catecholamine secretion in brown and white adipose tissues to stimulate thermogenesis. In the prevailing model of thermogenesis in warm-blooded animals, when the hypothalamus senses cold temperatures it triggers noradrenaline release to coordinate the cellular program of adaptive thermogenesis in white and brown adipose tissues. By contrast, this paper shows that when mice are exposed to cold, it is the interleukin-4-mediated activation of adipose tissue macrophages that releases noradrenaline and other catecholamines. Thus the cells of the haematopoietic system, such as alternatively activated macrophages, may constitute a second circuit for controlling non-shivering thermogenesis acting in parallel with the sympathetic nerves. All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments1,2,3. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue4,5. Acting via the β3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7,8,9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.