Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis - PubMed (original) (raw)

Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

Khoa D Nguyen et al. Nature. 2011.

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.

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Figures

Figure 1

Figure 1. Exposure to cold environment induces alternative activation of adipose tissue macrophages

a, b, Real time-PCR analysis of markers of alternative and classical activation in BAT (a) and WAT (b) of wild type (WT) mice chronically housed at 30 °C, 22 °C, or acutely subjected to a 4 °C from 22 °C (n=4 per temperature). Expression of all genes is normalized to their relative expression at 30 °C in WT mice. c-e, Expression of alternative activation markers Arg-1, CD206, and CD301 was monitored by flow cytometry in BAT (c, d) and WAT (e) macrophages of wild type (WT), IL4/IL13−/−, and STAT6−/− mice housed at 30 °C, 22 °C, and 4 °C (n=4-5 per genotype and temperature). f, Alternative activation of tissue macrophages was monitored at 22 °C and 4 °C by quantifying expression of CD301. BM (bone marrow). *P < 0.05, **P < 0.01, ***P < 0.001 comparison between WT at 30 °C and 22 °C, or between 22 °C and 4 °C. φP < 0.05, φφφP < 0.001 comparison between WT and various knockout mice at the same temperature.

Figure 2

Figure 2. Cold-induced metabolic adaptations require alternatively activated macrophages

a, Core body temperature of WT, IL4/IL13−/−, and STAT6−/− mice during a cold challenge at 4°C (n=8 per genotype and temperature). b, c, Real-time PCR analysis of thermogenic genes in BAT of WT, IL4/IL13−/−, and STAT6−/− mice housed at 30 °C, 22 °C or subjected to 4 °C cold challenge (n=4-5 per genotype and temperature). Expression of all genes is normalized to their relative expression at 30 °C in WT mice. d, Expression of alternatively activated mRNAs in BAT of IL4RαL/L and IL4RαL/LLysMCre mice housed at various temperatures (n=5 per genotype and temperature). e, Core body temperature of IL4RαL/L and IL4RαL/LLysMCre mice during exposure to 4 °C (n=5-6 per genotype and temperature). f, BAT of IL4RαL/L and IL4RαL/LLysMCre mice was analyzed by real-time PCR for expression of thermogenic and β-oxidation genes (n=5 per genotype and temperature). Expression of all genes is normalized to their relative expression at 30 °C in IL4RαL/L mice. g, Serum free fatty acid (FFA) levels in WT, IL4/IL13−/−, and STAT6−/− mice housed at 30 °C, 22 °C, and 4 °C (n=5-8 per genotype). h, Serum FFAs in IL4RαL/L and IL4RαL/LLysMCre mice housed at the three temperatures (n=5-11 per genotype). i, Representative gross and microscopic (haematoxylin and eosin staining) histology and of BAT from WT, IL4/IL13−/−, and STAT6−/− mice at 22 °C and after exposure to 4°C for 6 hours. j, Representative gross and microscopic (haematoxylin and eosin staining) histology of BAT from IL4RαL/L and IL4RαL/LLysMCre mice at 22 °C and after 6 hour exposure to 4°C. k, Immunoblot analysis for serine phosphorylated perilipin, total perilipin, serine phosphorylated-HSL and total HSL in 3T3-L1 adipocytes treated with PIA, CL-316243, IL4 or macrophage conditioned medium (± IL4 and AMPT) for 15 min. PIA (N6-phenylisopropyl adenosine), AMPT (α-methyl-p-tyrosine). l, Glycerol release by 3T3-L1 adipocytes after 6h treatment with PIA, CL-316243 (CL), IL4 or macrophage conditioned medium (n=5-7). *P < 0.05, **P < 0.01, ***P < 0.001 compared to comparison between WT or IL4RαL/L at 30 °C and those at 22 °C, or at 22 °C and 4 °C. φP < 0.05, φφP < 0.01, φφφP < 0.001 comparison between knockouts and WT or IL4RαL/L at the same temperature.

Figure 3

Figure 3. Alternatively activated macrophages produce catecholamines

a, Expression of tyrosine hydroxylase in WT and STAT6−/− peritoneal macrophages treated with vehicle (veh) or IL4, n=5 per genotype and condition. b, Noradrenaline secretion by WT and STAT6−/− bone-marrow-derived macrophages stimulated with IL4 or LPS (n=5 per genotype and condition). c, e Tyrosine hydroxylase expression in BAT (c) and WAT (e) macrophages of WT and STAT6−/− mice at 30 °C, 22 °C and 4 °C (n=5 per genotype and temperature). d, f, Noradrenaline content of BAT (d) and WAT (f) at 22 °C and 4 °C of WT and STAT6−/− mice (n=4-5 per genotype and temperature). *P < 0.05, **P < 0.01, ***P < 0.001 compared to WT. φP < 0.05, φφP < 0.01, φφφP < 0.001 compared to WT with IL4 at 4 °C samples.

Figure 4

Figure 4. Alternative activation of macrophages increases energy expenditure

a,b, Expression of alternative activation marker CD301 (a) and TH (b) in adipose tissue macrophages from IL4RαL/L and IL4RαL/LLysMCre mice treated with vehicle (Veh) or IL4 for 6 hours at 22 °C (n=4-5 per genotype and condition). c, Real-time PCR for thermogenic genes in BAT of IL4RαL/L and IL4RαL/LLysMCre mice treated with Veh or IL4 for 6 hours at 22 °C (n=4-5 per genotype and condition). d, Serum free fatty acid (FFA) levels in IL4RαL/L and IL4RαL/LLysMCre mice treated with Veh or IL4 for 6 hours at 22 °C (n=4-5 per genotype and condition). e, f, Quantification of energy expenditure in IL4RαL/L and IL4RαL/LLysMCre mice treated with vehicle (Veh) or IL4 (n=7-9 per genotype and condition). (e) Oxygen consumption (VO2) and (f) respiratory exchange ratio (RER). g, h, Quantification of energy expenditure in WT mice after macrophage depletion (n=8 per condition). Mice were injected with empty liposomes (Lipo) or clodronate-containing liposomes (Clod) 24 hours prior to energy expenditure studies. All data were collected during the light cycle. *P < 0.05, **P < 0.01, ***P < 0.001 compared to IL4RαL/L with Veh. φP < 0.05, φφP < 0.01, φφφP < 0.001 compared to IL4RαL/L with IL4.

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