An anti-obesity immunotherapy?

Adipose tissue-resident macrophages promote lipid storage in mice and can be stopped with antibody treatment

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 adipoinflammation and metabolic diseases associated with obesity. However, a defined role for adipose tissue-resident macrophages in energy storage has remained elusive. On page XXX of this issue, Cox et al. (1) convincingly and elegantly 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 orthologue, Pvf1. This study introduces a novel, macrophage-centred paradigm in metazoan energy storage.

Adipose tissue macrophages are a heterogeneous population and are pleiotropic in their functions. They can be broadly categorized into either adipose tissue resident macrophages and recruited, bone-marrow/monocyte derived macrophages. Tissue-resident macrophages are thought to be seeded during embryonic haematopoiesis and are transcriptionally distinct, long lived, self-renewing cells (2). Bone marrow-derived macrophages are recruited to the adipose tissue in response to chemotactic and inflammatory signals, a process accelerated in obesity. Recruitment of these macrophages is dependent on expression of the chemokine receptor CCR2, which is necessary for monocyte egress from the bone marrow (3). Studies in which CCR2 expression is disrupted indicate that these cells are responsible for adipose tissue inflammation, hepatic steatosis, and the predisposition to type 2 diabetes that come with obesity (4–7). However, CCR2 silencing does not prevent weight gain or adipocyte hypertrophy in response to high fat diet (HFD)-feeding (1, 4). In contrast, global macrophage depletion via strategies that target the CSF-1/CSF-1R axis results in reduced adipocyte and adipose tissue size (1, 8, 9), though these reports did not document food intake and so the effects could have been due to malaise/cachexia. Nevertheless, taken collectively, these findings indicated that CCR2-independent macrophages may play a role in the regulation of energy storage.

Building on these observations and capitalising on the conserved evolutionary nature of macrophages, Cox and colleagues (1) utilised a drosophila-based screen which indicated that hemocytes (drosophila macrophages) control lipid storage. Using this screen, Cox et al. screened conserved macrophage-borne factors for effects on lipid storage. Global and macrophage-specific genetic knockdown of drosophila PDGF-and-VEGF-related factor 3 (Pvf3) and its receptor Pvr diminished lipid storage in drosophila fat-body cells.

Translating this finding to rodents, the authors showed that the murine Pvf3 ortholog PDGFc was expressed most prominently in an embryo-derived subset of adipose tissue macrophages. A different CCR2-dependent macrophage subset were responsible for HFD-induced expression of pro-inflammatory genes. Tellingly, PDGFc was also upregulated upon high fat diet feeding in a CSF1R-dependent and CCR2-independent manner. Macrophage-specific knockout of Pdgfc reduced white adipocyte tissue weight, adipocyte size, and lipid content. Antibody-mediated PDGFcc inhibition suppressed HFD-induced weight gain to levels comparable to lean, normal diet-fed controls; an effect mediated by diminished adipose tissue size and adipocyte lipid content. Importantly, the resistance to obesity was not mediated by reduced caloric intake, but rather increased energy expenditure in the anti-PDGFcc-treated mice, giving a glimpse of the potential therapeutic relevance of this discovery.

Some may have contended, prior to this study, that while macrophages are implicated in obesity’s comorbidities of systemic inflammation and metabolic dysfunction, they likely do not play causal roles in organismal metabolism, pointing to the lack of efficacy of anti-inflammatory therapies in preventing obesity (10, 11). However, this is not the first study to implicate macrophages playing a causal role in energy storage and HFD-induced weight gain.

Adipose tissue-residing sympathetic neuron-associated macrophages contribute to obesity by importing and catabolizing norepinephrine (12), a lipolytic agent, in an inflammasome and age-dependent manner (13). However, these macrophages likely do not mediate the effects seen in this paper as they do not express Pdgfc (accession code: GSE103847). 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).

Nonetheless, this report by Cox and colleagues (1) is significant for its discovery of an adipose tissue macrophage-derived factor, PDGFcc, that directly controls energy storage in white adipocytes. Moreover, this study is notable for its careful discrimination of the roles of embryo-derived resident macrophages versus CCR2-dependent recruited macrophages in the contexts of energy storage, inflammation, and obesity. This study bunks the outdated M1/M2 model of macrophage polarisation and promotes a model, at least in mice, in which adipose-resident macrophages behave homeostatically to sense elevated organismal nutritional status and promote energy storage, whereas the recruited macrophages are responsible for the inflammation and metabolic syndrome that characterise obesity. It would be fascinating to explore the extent to which this paradigm remains applicable in other tissues and inflammatory conditions. Nevertheless, in this field 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.

Resident adipose tissue macrophages (RATMs) control lipid storage via production of PDGFcc.

In early life and in response to over nourishment, RATMs (green cells) upregulate PDGFcc production which induces lipid retention in white adipose tissue adipocytes in a paracrine manner, though the precise mechanism remains unclear. This action of RATMs is distinct from their recruited CCR2-dependent counterparts. These macrophages (red cells) are responsible for the pro-inflammatory cytokine expression that characterises obese adipose tissue. Treatment with anti-PDGFcc antibodies results in the restoration of homeostasis, with reduced lipid storage, smaller adipocyte size, and a reduction in body weight which is independent of food intake. Excess lipids are redirected towards the liver and towards thermogenesis in brown adipose tissue.