Diet-regulated production of PDGFcc by macrophages controls energy storage

doi:10.1126/science.abe9383

GSTDTAP > 气候变化

DOI	10.1126/science.abe9383
	Diet-regulated production of PDGFcc by macrophages controls energy storage
	Nehemiah Cox; Lucile Crozet; Inge R. Holtman; Pierre-Louis Loyher; Tomi Lazarov; Jessica B. White; Elvira Mass; E. Richard Stanley; Olivier Elemento; Christopher K. Glass; Frederic Geissmann
	2021-07-02
发表期刊	Science
出版年	2021
英文摘要	Recent work has suggested that macrophages may regulate adiposity, but the mechanisms underlying this process remain unresolved. Cox et al. report that a macrophage-derived growth factor, Pvf3, and its receptor on fat body cells are needed for lipid storage in fruit fly larvae (see the Perspective by O'Brien and Domingos). The mouse Pvf3 ortholog, PDGFcc, was similarly required to store fat in newborn and adult mice. When PDGFcc was blocked or deleted, food intake and absorption were normal, but mice increased their energy expenditure partly due to enhanced brown adipose tissue thermogenesis. PDGFcc was produced exclusively by fat-resident macrophages rather than by those mediating inflammation and insulin resistance. This work may inform future treatments for lipodystrophy, cachexia, and obesity. Science , abe9383, this issue p. [eabe9383][1]; see also abj5072, p. [24][2] ### INTRODUCTION To accommodate daily and seasonal variation in caloric intake, metazoans have evolved specialized tissues dedicated to dynamic storage and release of energy. Excessive or impaired energy storage in these adipose tissues results in obesity, lipodystrophy, or cachexia, and impairs organismal homeostasis. Adipose tissues consist of fat-storing adipocytes, supporting stromal cells, and immune cells. Adipocytes dynamically accumulate or release lipids in late embryos and during the postnatal period. Stromal cells include tissue macrophages, which are tightly associated with adipocytes across the animal kingdom from Drosophila to humans. Landmark studies have demonstrated that in the obese state, monocyte-derived macrophages are recruited into tissues via C-C chemokine receptor type 2 (CCR2) and produce cytokines such as tumor necrosis factor (TNF) that cause systemic inflammation, ectopic lipid storage, and insulin resistance. However, neither CCR2 nor monocytes appear to regulate fat mass or adiposity on their own. Recent observations in several models suggest that macrophages may also control adiposity, although their actual function and the underlying cellular and molecular mechanisms remain poorly understood. ### RATIONALE Macrophages are phagocytes that can eliminate unfit cells, microorganisms, and metabolic waste, and produce a large range of bioactive molecules and growth factors. In addition to monocyte-derived macrophages—which are the short-lived progeny of hematopoietic stem cells in vertebrates—most animals possess long-lived tissue macrophages. In mice, these cells originate from early mesodermal erythromyeloid progenitors, which invade the embryo proper soon after gastrulation and represent a foundational cell type within most organ anlagen. Resident macrophages serve tissue-specific purposes. For example, osteoclasts are critical for the development and remodeling of bones, whereas microglia in the central nervous system support neuronal circuit development, Kupffer cells scavenge blood particles and dying red blood cells in the liver, and alveolar macrophages uptake surfactant and remove airborne pollutants and microbes from the airways. We therefore hypothesized that resident macrophages associated with fat-storing cells may also support their function. In this study, we took advantage of the presence of equivalent cell types and orthologous genes in Drosophila and mice to identify a conserved molecular mechanism that mediates the control of adiposity and energy storage in metazoans by macrophages. ### RESULTS Using a combination of genetic and pharmacological approaches, we found that resident macrophage deficiency prevents storage of lipids in adipocytes from wild-type and Ccr2 –/– mice fed a high-fat diet, as well as hyperphagic leptin receptor–deficient mice. Moreover, we observed that macrophage deficiency impairs lipid storage in newborn mice and Drosophila larvae. Thus, we carried out a genetic screen in Drosophila and discovered that the macrophage-derived PDGF/VEGF-family growth factor Pvf3 and its receptor on fat-body cells are required for lipid storage in Drosophila larvae. We next identified the mouse Pvf3 ortholog PDGFcc, which controls lipid storage in mouse adipocytes. PDGFcc was produced by fat-resident macrophages in a diet-regulated manner and acted on subcutaneous and visceral white adipocytes in an adipose tissue–autonomous manner to control lipid storage in newborn and adult mice. PDGFcc blockade or deficiency did not affect food intake and absorption but resulted in increased energy expenditure at the organismal level, in part via increased thermogenesis in brown adipose tissue. This function of fat-resident macrophages was distinct from that of CCR2-dependent monocyte-derived macrophages, which mediate systemic inflammation and insulin resistance in obese mice and do not produce PDGFcc. ### CONCLUSION Our data identify an evolutionarily conserved function of adipose tissue–resident macrophages that couples energy intake with fat storage in adipocytes through the production of PDGFcc and independently from inflammation promoted by CCR2-dependent macrophages. By promoting energy storage over expenditure in neonates and adults, the production of PDGFcc by resident macrophages appears to regulate or buffer the systemic availability of lipids for metabolic purposes. These findings may be conducive to the design of pharmacological interventions in obesity, lipodystrophy, and cachexia. ![Figure][3] Parsimony diagram for the control of adiposity by macrophages. Fat-resident macrophages produce PDGFcc in response to diet, which increases lipid storage by white adipocytes (red arrows). PDGFcc blockade, in contrast, results in reduced lipid storage by adipocytes, and lipids not stored are redirected toward increased thermogenesis in brown adipose tissue (blue arrow). On the other hand, monocyte-derived macrophages recruited to hypertrophic adipocytes produce TNF and interleukin (IL)–1β, which mediate hepatosteatosis and insulin resistance (black arrows). The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)–family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue–resident macrophages, controls lipid storage in adipocytes in a leptin receptor– and C-C chemokine receptor type 2–independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans. [1]: /lookup/doi/10.1126/science.abe9383 [2]: /lookup/doi/10.1126/science.abj5072 [3]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334181
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Nehemiah Cox,Lucile Crozet,Inge R. Holtman,et al. Diet-regulated production of PDGFcc by macrophages controls energy storage[J]. Science,2021.
APA	Nehemiah Cox.,Lucile Crozet.,Inge R. Holtman.,Pierre-Louis Loyher.,Tomi Lazarov.,...&Frederic Geissmann.(2021).Diet-regulated production of PDGFcc by macrophages controls energy storage.Science.
MLA	Nehemiah Cox,et al."Diet-regulated production of PDGFcc by macrophages controls energy storage".Science (2021).