title: Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis.
abstract: All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments. 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 tissue. Acting via the β(3)-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes, 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 adipocytes. 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.
authors.affiliation: Immunology Program, Stanford University, Palo Alto, California 94305, USA.
authors.forename: Khoa D
authors.initials: KD
authors.lastname: Nguyen
authors.forename: Yifu
authors.initials: Y
authors.lastname: Qiu
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Cui
authors.forename: Y P Sharon
authors.initials: YP
authors.lastname: Goh
authors.forename: Julia
authors.initials: J
authors.lastname: Mwangi
authors.forename: Tovo
authors.initials: T
authors.lastname: David
authors.forename: Lata
authors.initials: L
authors.lastname: Mukundan
authors.forename: Frank
authors.initials: F
authors.lastname: Brombacher
authors.forename: Richard M
authors.initials: RM
authors.lastname: Locksley
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001831:Body Temperature / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism*; D002478:Cells, Cultured; D003080:Cold Temperature; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013312:Stress, Physiological / Q000502:physiology*; D022722:Thermogenesis / Q000502:physiology*; D020298:U937 Cells
chemical_list: D002395:Catecholamines; D015847:Interleukin-4
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