An anti-obesity immunotherapy?

doi:10.1126/science.abj5072

GSTDTAP > 气候变化

DOI	10.1126/science.abj5072
	An anti-obesity immunotherapy?
	Conan J. O. O'Brien; Ana Domingos
	2021-07-02
发表期刊	Science
出版年	2021
英文摘要	Energy storage is a crucial physiological process for all metazoans, the mechanisms of which are at least partially conserved across the animal kingdom. Lipid-storing adipocytes, the major constituent cell type of adipose tissues, are specialized for the storage of energy in the form of lipid triglycerides. Macrophages are an evolutionarily conserved immune cell population and are the most abundant immunocyte in obese adipose tissue. Recruited monocyte-derived macrophages have long been implicated in promoting the adipose tissue inflammation and metabolic diseases associated with obesity. However, a defined role for adipose tissue–resident macrophages in energy storage has remained elusive. On page 74 of this issue, Cox et al. ([ 1 ][1]) demonstrate that adipose-resident macrophages—through a conserved mechanism—directly regulate energy storage in adipocytes through the mammalian platelet-derived growth factor PDGFc and its Drosophila melanogaster ortholog, PDGF- and VEGF-related factor 3 ( Pvf3 ). This study introduces a new, macrophage-centered paradigm in metazoan energy storage. Adipose tissue macrophages are a heterogeneous population with varied and diverse functions. They can be broadly categorized into either adipose tissue–resident macrophages or recruited bone marrow– and monocyte-derived macrophages. Tissue-resident macrophages are thought to be seeded during embryonic hematopoiesis and are transcriptionally distinct, long-lived, and self-renewing cells ([ 2 ][2]). Bone marrow–derived macrophages are recruited to adipose (and other) tissues in response to chemotactic and inflammatory signals—a process that is accelerated in obesity. Recruitment of these macrophages is dependent on expression of the C-C chemokine receptor type 2 (CCR2), which is necessary for monocyte egress from the bone marrow ([ 3 ][3]). Studies in which CCR2 expression is disrupted indicate that these cells are responsible for adipose tissue inflammation, hepatic steatosis (fat accumulation in the liver), and the predisposition to type 2 diabetes, all of which are associated with obesity ([ 4 ][4]–[ 7 ][5]). However, CCR2 silencing in mice does not prevent weight gain or adipocyte hypertrophy in response to high-fat diet (HFD) feeding ([ 1 ][1], [ 4 ][4]). By contrast, global macrophage (recruited and tissue-resident) depletion through strategies that target the colony-stimulating factor 1 (CSF1)–CSF1 receptor (CSF1R) axis results in reduced adipocyte and adipose tissue size ([ 1 ][1], [ 8 ][6], [ 9 ][7]), although these studies did not document food intake, so the effects could have been due to malaise and/or cachexia (muscle wasting). Nevertheless, collectively these findings indicate that CCR2-independent macrophages may play a role in the regulation of energy storage. ![Figure][8] Targeting adipose tissue–resident macrophages Adipose tissue–resident macrophages control lipid storage through the production of platelet-derived growth factor (PDGFcc), which induces lipid retention in white adipose tissue adipocytes in a paracrine manner, although the precise mechanism is unclear. Recruited macrophages are responsible for the inflammation that characterizes obese adipose tissue. Treatment of mice with PDGFcc antibodies restores homeostasis and reduces lipid storage and body weight, redirecting excess lipids mostly to thermogenesis. GRAPHIC: V. ALTOUNIAN/ SCIENCE Building on these observations and capitalizing on the conserved evolutionary nature of macrophages, Cox et al. undertook a D. melanogaster –based screen, which revealed that hemocytes (macrophages in fruit flies) control lipid storage. The authors screened conserved macrophage-borne factors for effects on lipid storage, which led to the finding that macrophage-specific genetic ablation of Pvf3 and fat-body cell–specific deletion of its receptor Pvr diminished lipid storage in D. melanogaster fat-body cells—the fruit fly equivalent of mammalian adipocytes. Translating this finding to mice, Cox et al. showed that Pdgfc (the ortholog of Pvf3 ) was expressed most prominently in an embryo-derived subset of adipose tissue–resident macrophages. A different, non– Pdgfc -expressing CCR2-dependent macrophage subset was responsible for HFD-induced expression of proinflammatory genes. Tellingly, Pdgfc expression was also up-regulated upon HFD in a CSF1R-dependent and CCR2-independent manner. Macrophage-specific deletion of Pdgfc reduced white adipocyte tissue weight, adipocyte size, and lipid content in mice. Moreover, antibody-mediated PDGFcc (PDGFc forms a dimeric ligand) inhibition suppressed HFD-induced weight gain to amounts comparable to those observed in lean, normal diet–fed control mice—an effect mediated by diminished white adipose tissue size and adipocyte lipid content. Notably, the resistance to obesity was not mediated by reduced caloric intake, but rather increased energy expenditure in the anti–PDGFcc-treated mice, which gives a glimpse of the potential therapeutic relevance of this discovery. Treatment also enhanced brown adipose tissue thermogenesis and modestly increased liver lipid content, indicating that during treatment, as lipid storage in white adipocytes is inhibited, excess lipids are redirected to these sites for dissipation and storage of excess energy, respectively (see the figure). Prior to this study, some may have contended that although macrophages are implicated in systemic inflammation and metabolic dysfunction in obesity, they likely do not play causal roles (in organismal metabolism) owing to the lack of efficacy of anti-inflammatory therapies in preventing obesity ([ 10 ][9], [ 11 ][10]). However, this is not the first study to implicate macrophages as causal in energy storage and HFD-induced weight gain. Adipose tissue–residing sympathetic neuron–associated macrophages contribute to obesity by importing and catabolizing norepinephrine ([ 12 ][11]), a lipolytic agent, in an inflammasome- and age-dependent manner ([ 13 ][12]). However, these macrophages likely do not mediate the effects seen in the study of Cox et al. because they do not express Pdgfc ([ 12 ][11]). Similarly, Tribbles homolog 1–deficient mice have impaired macrophage differentiation and exhibit metabolic syndrome and a lipodystrophic phenotype with reduced white adipose tissue mass ([ 14 ][13]). The study of Cox et al. debunks the outdated M1-M2 model of macrophage polarization and promotes a model, at least in mice, in which adipose tissue–resident macrophages behave homeostatically to sense increased organismal nutritional status and promote energy storage, whereas the recruited macrophages are responsible for the inflammation and metabolic syndrome that characterize obesity. It will be fascinating to explore the extent to which this paradigm remains applicable in other tissues and inflammatory conditions. The biggest unanswered question centers on the extent to which the findings of Cox et al. will translate to humans. Single-cell RNA sequencing analysis indicates that human adipose tissue macrophages express PDGFC ([ 15 ][14]), although whether it performs the same function in humans as in mice is unknown. Future investigations should also probe the mechanism by which adipose tissue–resident macrophages sense nutritional status and the identity of the factors that prompt resident macrophages to express Pdgfc and promote energy storage. Nevertheless, this study has the potential to inform and inspire therapeutic strategies that could selectively and separately manipulate energy storage and the metabolic and inflammatory consequences of obesity. 1. [↵][15]1. N. Cox et al ., Science 373, eabe9383 (2021). [OpenUrl][16][Abstract/FREE Full Text][17] 2. [↵][18]1. E. Gomez Perdiguero, 2. F. Geissmann , Nat. Immunol. 17, 2 (2016). [OpenUrl][19][CrossRef][20][PubMed][21] 3. [↵][22]1. C.-L. Tsou et al ., J. Clin. Invest. 117, 902 (2007). [OpenUrl][23][CrossRef][24][PubMed][25][Web of Science][26] 4. [↵][27]1. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/334172
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Conan J. O. O'Brien,Ana Domingos. An anti-obesity immunotherapy?[J]. Science,2021.
APA	Conan J. O. O'Brien,&Ana Domingos.(2021).An anti-obesity immunotherapy?.Science.
MLA	Conan J. O. O'Brien,et al."An anti-obesity immunotherapy?".Science (2021).